Pesticidal compositions

ABSTRACT

A pesticidal composition comprising (a) a pesticidal effective amount of at least one compound of formula I in which Q is i or ii or iii or an agrochemically acceptable salt or an N-oxide thereof, and (b) a plant growth regulator, where the ratio of compound of formula I to plant growth regulator is from 20:1 to 1:25.

The present invention relates to new pesticidal, in particularinsecticidal, acaricidal, molluscicidal and nematicidal compositions andto methods of using them to combat and control pests such as insect,acarine, mollusc and nematode pests.

The present invention relates to a pesticidal composition comprising

(a) a pesticidal effective amount of at least one compound of formula I

in which Q isi or ii or iii

X, Y and Z independently of each other are C₁₋₄alkyl, C₃₋₆cycloalkyl,C₁₋₄haloalkyl, C₁₋₄ alkoxy, halogen, phenyl or phenyl substituted byC₁₋₄alkyl, C₁₋₄haloalkyl, halogen or cyano;m and n, independently of each other, are 0, 1, 2 or 3 and m+n is 0, 1,2 or 3;G is hydrogen, a metal, an ammonium, a sulfonium or a latentiatinggroup;R is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆cyanoalkyl, benzyl,C₁₋₄alkoxy(C₁₋₄)alkyl, C₁₋₄alkoxy(C₁₋₄)alkoxy(C₁₋₄)alkyl or a groupselected from G;A is C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl(C₁₋₄)alkyl, or C₃₋₆cycloalkyl-(C₁₋₄)alkyl where in thecycloalkyl moiety a methylene group is replaced by O, S or NR₀, where R₀is C₁₋₆alkyl or C₁₋₆alkoxy, or A is C₂₋₆alkenyl, C₂₋₆haloalkenyl,C₃₋₆alkynyl, C₁₋₆cyanoalkyl, benzyl, C₁₋₄alkoxy(C₁₋₄)alkyl,C₁₋₄alkoxy(C₁₋₄)alkoxy(C₁₋₄)alkyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,C₃₋₆cycloalkylcarbonyl, N-di(C₁₋₆alkyl)carbamoyl, benzoyl,C₁₋₆alkylsulfonyl, phenylsulfonyl, C₁₋₄alkylthio(C₁₋₄alkyl,C₁₋₄alkylsulfinyl(C₁₋₄)alkyl or C₁₋₄alkylsulfonyl(C₁₋₄)alkyl; and when Qis ii A may also be hydrogen, furanyl-(C₁₋₄alkyl,tetrahydro-thiofuranyl, tetrahydro-thiopyranyl or1-(C₁₋₄alkoxy-piperidin-4-yl; andR₁, R₂, R₃ and R₄, independently of each other, are hydrogen or methyl;or an agrochemically acceptable salt or an N-oxide thereof, and(b) a plant growth regulator, where the ratio of compound of formula Ito plant growth regulator is from 20:1 to 1:25.

It is usually expected that crops treated with a plant growth regulatorshow the same or even increased phytotoxic damages when exposed to apesticide compared to the untreated crop. Surprisingly, it has now beenfound that the application of a compound of the formula I and a plantgrowth regulator to the crops can reduce these phytotoxic damages of thecrops significantly.

In the compounds of the formula I, each alkyl moiety either alone or aspart of a larger group is a straight or branched chain and is, forexample, methyl, ethyl, n-propyl, n-butyl, iso-propyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, iso-pentyl and n-hexyl.

Alkoxy groups preferably have a preferred chain length of from 1 to 4carbon atoms. Alkoxy is, for example, methoxy, ethoxy, propoxy,i-propoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Such groupscan be part of a larger group such as alkoxyalkyl and alkoxyalkoxyalkyl.Alkoxyalkyl groups preferably have a chain length of 1 to 4 carbonatoms. Alkoxyalkyl is, for example, methoxymethyl, methoxyethyl,ethoxymethyl, ethoxyethyl, n-propoxymethyl, n-propoxyethyl orisopropoxymethyl.

Halogen is generally fluorine, chlorine, bromine or iodine. This alsoapplies, correspondingly, to halogen in combination with other meanings,such as haloalkyl.

Haloalkyl groups preferably have a chain length of from 1 to 6 carbonatoms. Haloalkyl is, for example, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl,1,1-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and2,2,2-trichloroethyl; preferably trichloromethyl, difluorochloromethyl,difluoromethyl, trifluoromethyl and dichlorofluoromethyl.

The cycloalkyl groups preferably have from 3 to 6 ring carbon atoms, forexample cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In theserings, a methylene group can be replaced by an oxygen and/or sulphuratom, which leads, for example, to oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, furanyl, tetrahydro-thiofuranyl andtetrahydro-thiopyranyl rings.

Phenyl, also as part of a substituent such as benzyl, may besubstituted, preferably by alkyl, haloalkyl or halogen groups. In thiscase, the substituents can be in ortho, meta and/or para position. Thepreferred substituent positions are the ortho and para positions to thering attachment point.

The latentiating groups G are selected to allow its removal by one or acombination of biochemical, chemical or physical processes to affordcompounds of formula I where G is hydrogen before, during or followingapplication to the treated area or plants. Examples of these processesinclude enzymatic cleavage, chemical hydrolysis and photoloysis.Compounds bearing such groups G may offer certain advantages, such asimproved penetration of the cuticula of the plants treated, increasedtolerance of crops, improved compatibility or stability in formulatedmixtures containing other herbicides, herbicide safeners, plant growthregulators, fungicides or insecticides, or reduced leaching in soils.

Such latentiating groups are known in the art, for example, fromWO08/071,405 and WO09/074,314, WO09/049,851, WO10/063,670 andWO10/066,780.

In particular, the latentiating group G is a group —C(X^(a))—R^(a) or—C(X^(b))—X^(c)—R^(b), and X^(a), R^(a), X^(b), X^(c) and R^(b) are asdefined above. wherein X^(a), X^(b) and X^(c) are independently of eachother oxygen or sulfur; R^(a) is H, C₁-C₁₈alkyl, C₂-C₁₈alkenyl,C₂-C₁₈alkynyl, C₁-C₁₀haloalkyl, C₁-C₁₀cyanoalkyl, C₁-C₁₀nitroalkyl,C₁-C₁₀aminoalkyl, C₁-C₅alkylaminoC₁-C₅alkyl,C₂-C₈dialkylaminoC₁-C₅alkyl, C₃-C₇cycloalkylC₁-C₅alkyl,C₁-C₅alkoxyC₁-C₅alkyl, C₃-C₅alkenyloxyC₁-C₅alkyl,C₃-C₅alkynylC₁-C₅oxyalkyl, C₁-C₅alkylthioC₁-C₅alkyl,C₁-C₅alkylsulfinylC₁-C₅alkyl, C₁-C₅alkylsulfonylC₁-C₅alkyl,C₂-C₈alkylideneaminoxyC₁-C₅alkyl, C₁-C₅alkylcarbonylC₁-C₅alkyl,C₁-C₅alkoxycarbonylC₁-C₅alkyl, aminocarbonylC₁-C₅alkyl,C₁-C₅alkylaminocarbonylC₁-C₅alkyl, C₂-C₈dialkylaminocarbonylC₁-C₅alkyl,C₁-C₅alkylcarbonylaminoC₁-C₅alkyl,N—C₁-C₅alkylcarbonyl-N—C₁-C₅alkylaminoC₁-C₅alkyl,C₃-C₆trialkylsilylC₁-C₅alkyl, phenylC₁-C₅alkyl (wherein the phenyl mayoptionally be substituted by C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃alkylsulfinyl, C₁-C₃alkylsulfonyl,halogen, cyano, or by nitro), heteroarylC₁-C₅alkyl, (wherein theheteroaryl may optionally be substituted by C₁-C₃alkyl, C₁-C₃haloalkyl,C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃alkylsulfinyl,C₁-C₃alkylsulfonyl, halogen, cyano, or by nitro), C₂-C₅haloalkenyl,C₃-C₈cycloalkyl, phenyl or phenyl substituted by C₁-C₃alkyl,C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, halogen, cyano or nitro,heteroaryl or heteroaryl substituted by C₁-C₃ alkyl, C₁-C₃haloalkyl,C₁-C₃alkoxy, C₁-C₃haloalkoxy, halogen, cyano or nitro, and

R^(b) is C₁-C₁₈alkyl, C₃-C₁₈alkenyl, C₃-C₁₈alkynyl, C₂-C₁₀haloalkyl,C₁-C₁₀cyanoalkyl, C₁-C₁₀nitroalkyl, C₂-C₁₀aminoalkyl,C₁-C₅alkylaminoC₁-C₅alkyl, C₂-C₈dialkylaminoC₁-C₅alkyl,C₃-C₇cycloalkylC₁-C₅alkyl, C₁-C₅alkoxyC₁-C₅alkyl,C₃-C₅alkenyloxyC₁-C₅alkyl, C₃-C₅alkynyloxyC₁-C₅alkyl,C₁-C₅alkylthioC₁-C₅alkyl, C₁-C₅alkylsulfinylC₁-C₅alkyl,C₁-C₅alkylsulfonylC₁-C₅alkyl, C₂-C₈alkylideneaminoxyC₁-C₅alkyl,C₁-C₅alkylcarbonylC₁-C₅alkyl, C₁-C₅alkoxycarbonylC₁-C₅alkyl,aminocarbonylC₁-C₅alkyl, C₁-C₅alkylaminocarbonylC₁-C₅alkyl,C₂-C₈dialkylaminocarbonylC₁-C₅alkyl, C₁-C₅alkylcarbonylaminoC₁-C₅alkyl,N—C₁-C₅alkylcarbonyl-N—C₁-C₅alkylaminoC₁-C₅alkyl, phenylC₁-C₅alkyl(wherein the phenyl may optionally be substituted by C₁-C₃alkyl,C₁-C₃haloalkyl, C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio,C₁-C₃alkylsulfinyl, C₁-C₃alkylsulfonyl, halogen, cyano, or by nitro),heteroarylC₁-C₅alkyl, (wherein the heteroaryl may optionally besubstituted by C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy,C₁-C₃alkyl-thio, C₁-C₃alkylsulfinyl, C₁-C₃alkylsulfonyl, halogen, cyano,or by nitro), C₃-C₅haloalkenyl, C₃-C₈cycloalkyl, phenyl or phenylsubstituted by C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy, C₃halo-alkoxy,halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C₁-C₃alkyl, C₁₋₃haloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, halogen, cyano ornitro,

It is preferred that G is hydrogen, a metal, preferably an alkali metalor alkaline earth metal, or an ammonium or sulfonium group, wherehydrogen is especially preferred.

Depending on the nature of the substituents, compounds of formula I mayexist in different isomeric forms. When G is hydrogen, for example,compounds of formula I may exist in different tautomeric forms:

This invention covers all isomers and tautomers and mixtures thereof inall proportions. Also, when substituents contain double bonds, cis- andtrans-isomers can exist. These isomers, too, are within the scope of theclaimed compounds of the formula I.

The invention covers also to the agriculturally acceptable salts whichthe compounds of formula I are able to form with transition metal,alkali metal and alkaline earth metal bases, amines, quaternary ammoniumbases or tertiary sulfonium bases.

Among the transition metal, alkali metal and alkaline earth metal saltformers, special mention should be made of the hydroxides of copper,iron, lithium, sodium, potassium, magnesium and calcium, and preferablythe hydroxides, bicarbonates and carbonates of sodium and potassium.

Examples of amines suitable for ammonium salt formation include ammoniaas well as primary, secondary and tertiary C₁-C₁₈alkylamines,C₁-C₄hydroxyalkylamines and C₂-C₄alkoxyalkyl-amines, for examplemethylamine, ethylamine, n-propylamine, i-propylamine, the fourbutylamine isomers, n-amylamine, i-amylamine, hexylamine, heptylamine,octylamine, nonylamine, decylamine, pentadecylamine, hexadecylamine,heptadecylamine, octadecylamine, methylethylamine, methylisopropylamine,methylhexylamine, methylnonylamine, methylpentadecylamine,methyloctadecylamine, ethylbutylamine, ethylheptylamine,ethyloctylamine, hexylheptylamine, hexyloctylamine, dimethylamine,diethylamine, di-n-propylamine, di-i-propylamine, di-n-butylamine,di-n-amylamine, di-i-amylamine, dihexylamine, diheptylamine,dioctylamine, ethanolamine, n-propanolamine, i-propanolamine,N,N-diethanolamine, N-ethylpropanolamine, N-butylethanolamine,allylamine, n-but-2-enylamine, n-pent-2-enylamine,2,3-dimethylbut-2-enylamine, dibut-2-enylamine, n-hex-2-enylamine,propylenediamine, trimethylamine, triethylamine, tri-n-propylamine,tri-i-opropylamine, tri-n-butylamine, tri-i-butylamine,tri-sec-butylamine, tri-n-amylamine, methoxyethylamine andethoxyethylamine; heterocyclic amines, for example pyridine, quinoline,isoquinoline, morpholine, piperidine, pyrrolidine, indoline,quinuclidine and azepine; primary arylamines, for example anilines,methoxyanilines, ethoxyanilines, o-, m- and p-toluidines,phenylenediamines, benzidines, naphthylamines and o-, m- andp-chloroanilines; but especially triethylamine, i-propylamine anddi-i-propylamine.

Preferred quaternary ammonium bases suitable for salt formationcorrespond, for example, to the formula [N(R_(a) R_(b) R_(c) R_(d))]OH,wherein R_(a), R_(b), R_(c) and R_(d) are each independently of theothers hydrogen or C₁-C₄alkyl. Further suitable tetraalkylammonium baseswith other anions can be obtained, for example, by anion exchangereactions.

Preferred tertiary sulfonium bases suitable for salt formationcorrespond, for example, to the formula [SR_(e)R_(f)R_(g)]OH, whereinR_(e), R_(f) and R_(g) are each independently of the others C₁-C₄ alkyl.Trimethylsulfonium hydroxide is especially preferred. Suitable sulfoniumbases may be obtained from the reaction of thioethers, in particulardialkylsulfides, with alkylhalides, followed by conversion to a suitablebase, for example a hydroxide, by anion exchange reactions.

It should be understood that in those compounds of formula I, where G isa metal, ammonium or sulfonium as mentioned above and as such representsa cation, the corresponding negative charge is largely delocalisedacross the O—C═C—C═O unit.

The compounds of formula I according to the invention also includehydrates which may be formed during the salt formation.

According to the present invention, compounds of formula I are used incombination with plant growth regulators preferably selected from:

Antiauxins, such as clofibric acid and 2,3,5-tri-iodobenzoic acid;Auxins, such as 4-CPA, 2,4-D, 2,4-DB, 2,4-DEP, Dichlorprop, fenoprop,IAA, IBA, Naphthaleneacetamide, α-naphthaleneacetic acid, 1-naphthol,naphthoxyacetic acids, MCPA-thioethyl, potassium naphthenate, sodiumnaphthenate and 2,4,5-T;Cytokinins, such as 2iP, Benzyladenine, 6-benzylaminopurine, kinetin andzeatin;Defoliants, such as calcium cyanamide, dimethipin, endothal, ethephon,merphos, metoxuron, pentachlorophenol, thidiazuron and tribufos;Ethylene inhibitors, such as aviglycine, 1-methylcyclopropene;Growth inhibitors, such as abscisic acid, ancymidol, butralin, carbaryl,chlorphonium, chlorpropham, dikegulac, flumetralin, fluoridamid,fosamine, gibberellic acid, glyphosine, isopyrimol, jasmonic acid,maleic hydrazide, mepiquat, piproctanyl, prohydrojasmon, propham,2,3,5-tri-iodobenzoic acid, morphactins [chlorfluren, chlorflurenol,dichlorflurenol, flurenol], tebuconazole, metconazole;Growth retardants, such as chlormequat, daminozide, flurprimidol,mefluidide, paclobutrazol, tetcyclacis and uniconazole;Growth stimulators, such as brassinolide, forchlorfenuron, hymexazol andthiametoxam;Unclassified plant regulators, such as azoxystrobin, benzofluor,buminafos, carvone, ciobutide, clofencet, cloxyfonac, cyanamide,cyclanilide, cycloheximide, cyprosulfamide, epocholeone, ethychlozate,fenridazon, heptopargil, holosulf, inabenfide, karetazan, lead arsenate,methasulfocarb, prohexadione, pydanon, sintofen, sulfometuron,triapenthenol and trinexapac;Plant activators, such as acibenzolar, acibenzolar-S-methyl andprobenazole;Salicylates, such as salicylic acid and sodium salicylate;Jasmonates such as jasmonic acid, methyl jasmonate and cis-jasmone;Plant peptide hormones such as systemin, CLV3/ESR-related (‘CLE’)peptide family, ENOD40, phytosulfokine, POLARIS, Rapid AlkalinizationFactor, SCR/SP11, ROTUNDIFOLIA4/DEVIL1, inflorescence deficient inabscission;further, polyamines; strigolactones and nitric oxide donors.

The preferred plant growth regulator is selected from trinexapac ethyl,ethephon, chlormequat, gibberellic acid, prohexadione, mepiquat,flumetralin, cyanamide, paclobutrazol, gibberellin, maleic hydrazide,tribufos, sulfometuron, uniconazole, forchlorfenuron, cyclanilide, 2.4D, MCPA-thioethyl, 1-methylcyclopropene, 6-benzylaminopurine andacibenzolar-S-methyl.

More preferably, the plant growth regulator used in the compositionsaccording to the invention is selected from trinexapac ethyl,1-methylcyclopropene, ethephon, chlormequat, and acibenzolar-S-methyl,and, even more preferably, from trinexapac ethyl, 1-methylcyclopropene,chlormequat and acibenzolar-S-methyl and in particular from trinexapacethyl and chlormequat, especially trinexapac ethyl andchlormequat-chloride.

Preferably, the ratio of compound of formula I to plant growth regulatorranges from 1:1 to 1:20, and more preferably from 1:10 to 1:20.

The above-mentioned plant growth regulators are described, for example,in the Pesticide Manual, Twelfth Edition, British Crop ProtectionCouncil, 2000, or other readily available resources.

Preferably, in the compounds of the formula I, the substituent R ishydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂-C₆alkenyl, C₃-C₆alkynyl, benzylor C₁₋₄alkoxy(C₁₋₄)alkyl, in particular hydrogen, methyl, ethyl,trifluoromethyl, allyl, propargyl, benzyl, methoxymethyl, ethoxymethylor methoxyethyl.

Preferably, X, Y and Z denote C₁-C₄alkyl, C₃-C₆cycloalkyl, C₁-C₄alkoxyor halogen, in particular methyl, ethyl, cyclopropyl, methoxy, fluoro,bromo or chloro, when m+n is 1-3, in particular, when m+n is 1-2.

Alternatively, Y and Z, independently of each other, denote C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁₋₄alkoxy, halogen, phenyl or phenyl substituted byC₁₋₄alkyl or halogen, in particular methyl, ethyl, cyclopropyl, methoxy,fluoro, chloro, bromo, phenyl or phenyl substituted with halogen, inparticular fluoro or chloro, in particular in 4-position, when m+n is1-3, in particular, when m+n is 1-2.

In the compounds of the formula I, the substituent A is preferablyC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄alkyl, orC₃₋₆cycloalkyl(C₁₋₄)alkyl where in the cycloalkyl moiety a methylenegroup is replaced by O, S or NR₀, where R₀ is C₁₋₆alkyl or C₁₋₆alkoxy,or A is C₂₋₆alkenyl, C₃₋₆alkynyl, benzyl, C₁₋₄alkoxy(C₁₋₄)alkyl,C₁₋₄alkoxy(C₁₋₄)alkoxy(C₁₋₄)alkyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl or C₁₋₄alkylthio(C₁₋₄)alkyl, in particular methyl,ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, oxetan-3-ylmethyl, tetrahydrofuran-2-ylmethyl,tetrahydropyran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylmethyl, allyl,propargyl, benzyl, methoxymethyl, ethoxymethyl, methoxyethyl,methoxypropyl, methoxyethoxymethyl, methoxymethoxyethyl, oxetanyl-3-yl,tetrahydrofuran-2-yl, tetrahydropyran-2-yl, tetrahydrofuran-3-yl,tetrahydropyran-4-yl or methylthioethyl;

when Q is ii, A may also preferably be hydrogen, furanyl(C₁₋₄alkyl,tetrahydro-thiofuranyl, tetrahydro-thiopyranyl or1-(C₁₋₄alkoxy-piperidin-4-yl, in particular hydrogen, furan-2-ylmethyl,furan-3-ylmethyl, tetrahydro-thiopyran-4-ylmethyl or1-methoxy-piperidin-4-yl.

In another preferred group of compounds of the formula (I), R ishydrogen, methyl, ethyl, trifluoromethyl, allyl, propargyl, benzyl,methoxymethyl, ethoxymethyl or methoxyethyl, X is methyl, ethyl,cyclopropyl, methoxy, fluoro, bromo or chloro, Y and Z, independently ofeach other, are methyl, ethyl, cyclopropyl, methoxy, fluoro, chloro,bromo, phenyl or phenyl substituted by halogen or C₁-C₂alkyl, G ishydrogen and A has the meanings assigned to it above.

In a particularly preferred group of compounds of the formula (I), R ismethyl, ethyl, allyl, propargyl, methoxymethyl, X is methyl, ethyl,cyclopropyl, methoxy, fluoro, bromo or chloro, Y and Z, independently ofeach other, are methyl, ethyl, cyclopropyl, methoxy, fluoro, chloro,bromo, phenyl or phenyl substituted by halogen or C₁-C₂alkyl, G ishydrogen and A has the meanings assigned to it above.

Preferably, Q is i or ii, more preferably i.

In a more preferred group of compounds of the formula (I), R is methyl,ethyl, methoxymethyl, X is methyl, ethyl, cyclopropyl, methoxy, fluoro,bromo or chloro, Y and Z, independently of each other, are methyl,ethyl, cyclopropyl, methoxy, fluoro, chloro, bromo, phenyl or phenylsubstituted by halogen or C₁-C₂alkyl, G is hydrogen and A is methyl,ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, 2-fluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, oxetan-3-ylmethyl, tetrahydrofuran-2-ylmethyl,tetrahydropyran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylmethyl, allyl,propargyl, benzyl, methoxymethyl, ethoxymethyl, methoxyethyl,methoxypropyl, methoxyethoxymethyl, methoxymethoxyethyl, oxetanyl-3-yl,tetrahydrofuran-2-yl, tetrahydropyran-2-yl, tetrahydrofuran-3-yl,tetrahydropyran-4-yl or methylthioethyl;

and when Q is ii, A is also hydrogen, furan-2-ylmethyl,furan-3-ylmethyl, tetrahydro-thiopyran-4-ylmethyl or1-methoxy-piperidin-4-yl.

Preferably, Q is i or iii, more preferably i.

It is preferred that when Q is iii, then R₁ to R₄ are hydrogen.

In another preferred group of compounds of the formula (I), R is methyl,X is methyl or methoxy, Y and Z, independently of each other, aremethyl, ethyl, methoxy, chloro or bromo, G is hydrogen, methoxycarbonylor propenyloxycarbonyl, and A is methyl, ethyl, methoxymethyl,tetrahydrofuran-2-yl or tetrahydrofuran-3-yl, and when Q is ii, A isalso hydrogen.

The compounds of the invention may be made by a variety of methods asdescribed in detail, for example, in WO09/049,851, WO10/063,670 andWO10/066,780.

The compounds I and, where appropriate, the tautomers thereof, in eachcase in free form or in salt form, can be present in the form of one ofthe isomers which are possible or as a mixture of these, for example inthe form of pure isomers, such as antipodes and/or diastereomers, or asisomer mixtures, such as enantiomer mixtures, for example racemates,diastereomer mixtures or racemate mixtures, depending on the number,absolute and relative configuration of asymmetric carbon atoms whichoccur in the molecule and/or depending on the configuration ofnon-aromatic double bonds which occur in the molecule; the inventionrelates to the pure isomers and also to all isomer mixtures which arepossible and is to be understood in each case in this sense hereinaboveand hereinbelow, even when stereochemical details are not mentionedspecifically in each case.

Diastereomer mixtures or racemate mixtures of compounds I, in free formor in salt form, which can be obtained depending on which startingmaterials and procedures have been chosen can be separated in a knownmanner into the pure diasteromers or racemates on the basis of thephysicochemical differences of the components, for example by fractionalcrystallization, distillation and/or chromatography.

Enantiomer mixtures, such as racemates, which can be obtained in asimilar manner can be resolved into the optical antipodes by knownmethods, for example by recrystallization from an optically activesolvent, by chromatography on chiral adsorbents, for examplehigh-performance liquid chromatography (HPLC) on acetyl celulose, withthe aid of suitable microorganisms, by cleavage with specific,immobilized enzymes, via the formation of inclusion compounds, forexample using chiral crown ethers, where only one enantiomer iscomplexed, or by conversion into diastereomeric salts, for example byreacting a basic end-product racemate with an optically active acid,such as a carboxylic acid, for example camphor, tartaric or malic acid,or sulfonic acid, for example camphorsulfonic acid, and separating thediastereomer mixture which can be obtained in this manner, for exampleby fractional crystallization based on their differing solubilities, togive the diastereomers, from which the desired enantiomer can be setfree by the action of suitable agents, for example basic agents.

Pure diastereomers or enantiomers can be obtained according to theinvention not only by separating suitable isomer mixtures, but also bygenerally known methods of diastereoselective or enantioselectivesynthesis, for example by carrying out the process according to theinvention with starting materials of a suitable stereochemistry.

It is advantageous to isolate or synthesize in each case thebiologically more effective isomer, for example enantiomer ordiastereomer, or isomer mixture, for example enantiomer mixture ordiastereomer mixture, if the individual components have a differentbiological α-tivity.

The compounds I and, where appropriate, the tautomers thereof, in eachcase in free form or in salt form, can, if appropriate, also be obtainedin the form of hydrates and/or include other solvents, for example thosewhich may have been used for the crystallization of compounds which arepresent in solid form.

The compounds according to the following Tables below can be preparedaccording to the methods described above.

TABLE 1 This table discloses the 132 compounds T1.001 to T1.132 of theformula Ia: (Ia)

wherein R is CH₃, A is CH₃, G is hydrogen and R_(a), R_(b), R_(c) andR_(d) are as defined below: No. R_(a) R_(b) R_(c) R_(d) T1.001 Br H H HT1.002 Cl H H H T1.003 CH₃ H H H T1.004 CH₂CH₃ H H H T1.005 OCH₃ H H HT1.006 Br Cl H H T1.007 Cl Br H H T1.008 Cl Cl H H T1.009 Cl CH₃ H HT1.010 CH₃ Cl H H T1.011 CH₃ CH₃ H H T1.012 Cl H Cl H T1.013 Cl H CH₃ HT1.014 Cl H CH₂CH₃ H T1.015 Cl H OCH₃ H T1.016 CH₃ H CH₃ H T1.017 CH₃ HCH₂CH₃ H T1.018 CH₃ H OCH₃ H T1.019 CH₂CH₃ H CH₂CH₃ H T1.020 CH₂CH₃ HOCH₃ H T1.021 OCH₃ H OCH₃ H T1.022 Br H H Cl T1.023 Br H H CH₃ T1.024 BrH H 4-Cl-C₆H₄ T1.025 Cl H H Cl T1.026 Cl H H CH₃ T1.027 Cl H H 4-Cl-C₆H₄T1.028 CH₃ H H Br T1.029 CH₃ H H Cl T1.030 CH₃ H H CH₃ T1.031 CH₃ H HC₆H₅ T1.032 CH₃ H H 4-Cl-C₆H₄ T1.033 CH₂CH₃ H H CH₃ T1.034 CH₂CH₃ H H4-Cl-C₆H₄ T1.035 OCH₃ H H CH₃ T1.036 OCH₃ H H 4-Cl-C₆H₄ T1.037 Cl H ClBr T1.038 CH₃ H CH₃ Br T1.039 CH₃ H CH₃ Cl T1.040 CH₃ H CH₃ 4-Cl-C₆H₄T1.041 Br Cl H CH₃ T1.042 Br CH₃ H CH₃ T1.043 Cl Cl H Cl T1.044 Cl Br HCH₃ T1.045 Cl Cl H CH₃ T1.046 Cl CH₃ H Cl T1.047 Cl CH₃ H CH₃ T1.048 CH₃Br H CH₃ T1.049 CH₃ Cl H CH₃ T1.050 CH₃ CH₃ H CH₃ T1.051 CH₃ CH₃ H4-Cl-C₆H₄ T1.052 Br Br CH₃ H T1.053 Br Cl CH₃ H T1.054 Br CH₃ Br HT1.055 Br CH₃ Cl H T1.056 Cl Br CH₃ H T1.057 Cl Cl Cl H T1.058 Cl Cl CH₃H T1.059 Cl CH₃ Cl H T1.060 Cl CH₃ CH₂CH₃ H T1.061 Cl CH₃ OCH₃ H T1.062Cl 4-Cl-C₆H₄ Cl H T1.063 Cl 4-Cl-C₆H₄ CH₃ H T1.064 Cl 4-Cl-C₆H₄ CH₂CH₃ HT1.065 Cl 4-Cl-C₆H₄ OCH₃ H T1.066 CH₃ Br CH₃ H T1.067 CH₃ Cl CH₃ HT1.068 CH₃ CH₃ Br H T1.069 CH₃ CH₃ Cl H T1.070 CH₃ CH₃ CH₃ H T1.071 CH₃CH₃ CH₂CH₃ H T1.072 CH₃ CH₃ OCH₃ H T1.073 CH₃ 4-Cl-C₆H₄ CH₃ H T1.074 CH₃4-Cl-C₆H₄ CH₂CH₃ H T1.075 CH₃ 4-Cl-C₆H₄ OCH₃ H T1.076 CH₂CH₃ Br Br HT1.077 CH₂CH₃ Br Cl H T1.078 CH₂CH₃ Br CH₃ H T1.079 CH₂CH₃ Br CH₂CH₃ HT1.080 CH₂CH₃ Br OCH₃ H T1.081 CH₂CH₃ Cl Br H T1.082 CH₂CH₃ Cl Cl HT1.083 CH₂CH₃ Cl CH₃ H T1.084 CH₂CH₃ Cl CH₂CH₃ H T1.085 CH₂CH₃ Cl OCH₃ HT1.086 CH₂CH₃ CH₃ Br H T1.087 CH₂CH₃ CH₃ Cl H T1.088 CH₂CH₃ CH₃ CH₂CH₃ HT1.089 CH₂CH₃ CH₃ OCH₃ H T1.090 CH₂CH₃ CH₂CH₃ CH₃ H T1.091 CH₂CH₃ CH₂CH₃CH₂CH₃ H T1.092 CH₂CH₃ 4-Cl-C₆H₄ Br H T1.093 CH₂CH₃ 4-Cl-C₆H₄ CH₂CH₃ HT1.094 CH₂CH₃ 4-Cl-C₆H₄ OCH₃ H T1.095 OCH₃ Br CH₃ H T1.096 OCH₃ Cl CH₃ HT1.097 OCH₃ CH₃ Br H T1.098 OCH₃ CH₃ Cl H T1.099 OCH₃ CH₃ OCH₃ H T1.100OCH₃ 4-Cl-C₆H₄ OCH₃ H T1.101 CH₃ CH₃ CH₃ F T1.102 CH₃ CH₃ CH₃ Cl T1.103CH₃ CH₃ CH₃ Br T1.104 CH₃ CH₃ CH₃ CH₃ T1.105 CH₃ CH₃ CH₃ 4-Cl-C₆H₄T1.106 Cl CH₃ CH₃ CH₃ T1.107 CH₃ Cl CH₃ CH₃ T1.108 CH₃ CH₃ Cl CH₃ T1.109CH₂CH₃ CH₃ CH₃ CH₃ T1.110 OCH₃ CH₃ CH₃ CH₃ T1.111 Cyclo-C3 CH₃ CH₃ CH₃T1.112 CH₃ CH₃ Cyclo-C3 H T1.113 CH₃ F H Br T1.114 CH₃ CH₃ H Br T1.115CH₂CH₃ CH₃ H CH₃ T1.116 OCH₃ CH₃ H CH₃ T1.117 Cyclo-C3 CH₃ H CH₃ T1.118CH₂CH₃ Cl H CH₃ T1.119 OCH₃ Cl H CH₃ T1.120 Cyclo-C3 Cl H CH₃ T1.121 ClH CH₃ CH₃ T1.122 CH₃ H CH₃ CH₃ T1.123 CH₂CH₃ H CH₃ CH₃ T1.124 OCH₃ H CH₃CH₃ T1.125 Cyclo-C3 H CH₃ CH₃ T1.126 F H Cl CH₃ T1.127 Cl H F CH₃ T1.128H CH₃ CH₃ CH₃ T1.129 Br CH₃ CH₃ CH₃ T1.130 CH₃ H Cl CH₃ T1.131 CH₃ H BrCH₃ T1.132 Br H CH₃ CH₃ Cyclo-C3 means cyclopropyl.

Table 2:

This table discloses the 132 compounds T2.001 to T2.132 of the formulaIa, wherein R is CH₃, A is CH₂CH₃, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 3:

This table discloses the 132 compounds T3.001 to T3.132 of the formulaIa, wherein R is CH₃, A is n-C₃H₇, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 4:

This table discloses the 132 compounds T4.001 to T4.132 of the formulaIa, wherein R is CH₃, A is i-C₃H₇, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 5:

This table discloses the 132 compounds T5.001 to T5.132 of the formulaIa, wherein R is CH₃, A is n-C₄H₉, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 6:

This table discloses the 132 compounds T6.001 to T6.132 of the formulaIa, wherein R is CH₃, A is i-C₄H₉, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 7:

This table discloses the 132 compounds T7.001 to T7.132 of the formulaIa, wherein R is CH₃, A is t-C₄H₉, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 8:

This table discloses the 132 compounds T8.001 to T8.132 of the formulaIa, wherein R is CH₃, A is cyclopropyl, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 9:

This table discloses the 132 compounds T9.001 to T9.132 of the formulaIa, wherein R is CH₃, A is cyclopentyl, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 10:

This table discloses the 132 compounds T10.001 to T10.132 of the formulaIa, wherein R is CH₃, A is cyclohexyl, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 11:

This table discloses the 132 compounds T11.001 to T11.132 of the formulaIa, wherein R is CH₃, A is 2,2-(CH₃)₂-propyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 12:

This table discloses the 132 compounds T12.001 to T12.132 of the formulaIa, wherein R is CH₃, A is allyl, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 13:

This table discloses the 132 compounds T13.001 to T13.132 of the formulaIa, wherein R is CH₃, A is CH₂—CH═C(CH₃)₂, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 14:

This table discloses the 132 compounds T14.001 to T14.132 of the formulaIa, wherein R is CH₃, A is CH₂—CH═C(Cl)₂, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 15:

This table discloses the 132 compounds T15.001 to T15.132 of the formulaIa, wherein R is CH₃, A is propargyl, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 16:

This table discloses the 132 compounds T16.001 to T16.132 of the formulaIa, wherein R is CH₃, A is CH₂C≡CCH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 17:

This table discloses the 132 compounds T17.001 to T17.132 of the formulaIa, wherein R is CH₃, A is CH₂-cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 18:

This table discloses the 132 compounds T18.001 to T18.132 of the formulaIa, wherein R is CH₃, A is CH₂CN, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 19:

This table discloses the 132 compounds T19.001 to T19.132 of the formulaIa, wherein R is CH₃, A is CH₂OCH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 20:

This table discloses the 132 compounds T20.001 to T20.132 of the formulaIa, wherein R is CH₃, A is CH₂OCH₂CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 21:

This table discloses the 132 compounds T21.001 to T21.132 of the formulaIa, wherein R is CH₃, A is CH₂CH₂OCH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 22:

This table discloses the 132 compounds T22.001 to T22.132 of the formulaIa, wherein R is CH₃, A is CH₂OCH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 23:

This table discloses the 132 compounds T23.001 to T23.132 of the formulaIa, wherein R is CH₃, A is CH₂CH₂OCH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 24:

This table discloses the 132 compounds T24.001 to T24.132 of the formulaIa, wherein R is CH₃, A is oxetan-3-yl, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 25:

This table discloses the 132 compounds T25.001 to T25.132 of the formulaIa, wherein R is CH₃, A is tetrahydrofuran-2-yl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 26:

This table discloses the 132 compounds T26.001 to T26.132 of the formulaIa, wherein R is CH₃, A is tetrahydrofuran-3-yl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 27:

This table discloses the 132 compounds T27.001 to T27.132 of the formulaIa, wherein R is CH₃, A is tetrahydropyran-2-yl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 28:

This table discloses the 132 compounds T28.001 to T28.132 of the formulaIa, wherein R is CH₃, A is tetrahydropyran-4-yl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 29:

This table discloses the 132 compounds T29.001 to T29.132 of the formulaIa, wherein R is CH₃, A is CH₂CH₂F, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 30:

This table discloses the 132 compounds T30.001 to T30.132 of the formulaIa, wherein R is CH₃, A is CH₂CHF₂, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 31:

This table discloses the 132 compounds T31.001 to T31.132 of the formulaIa, wherein R is CH₃, A is CH₂CF₃, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 32:

This table discloses the 132 compounds T32.001 to T32.132 of the formulaIa, wherein R is CH₃, A is benzyl, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 33:

This table discloses the 132 compounds T33.001 to T33.132 of the formulaIa, wherein R is CH₃, A is C(O)—CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 34:

This table discloses the 132 compounds T34.001 to T34.132 of the formulaIa, wherein R is CH₃, A is C(O)—OCH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 35:

This table discloses the 132 compounds T35.001 to T35.132 of the formulaIa, wherein R is CH₃, A is C(O)-cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 36:

This table discloses the 132 compounds T36.001 to T36.132 of the formulaIa, wherein R is CH₃, A is C(O)—N(CH₃)₂, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 37:

This table discloses the 132 compounds T37.001 to T37.132 of the formulaIa, wherein R is CH₃, A is C(O)—C₆H₅, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 38:

This table discloses the 132 compounds T38.001 to T38.132 of the formulaIa, wherein R is CH₃, A is SO₂CH₃, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 39:

This table discloses the 132 compounds T39.001 to T39.132 of the formulaIa, wherein R is CH₃, A is SO₂C₆H₅, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 40:

This table discloses the 132 compounds T40.001 to T40.132 of the formulaIa, wherein R is hydrogen, A is CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 41:

This table discloses the 132 compounds T41.001 to T41.132 of the formulaIa, wherein R is hydrogen, A is CH₂CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 42:

This table discloses the 132 compounds T42.001 to T42.132 of the formulaIa, wherein R is hydrogen, A is i-C₃H₇, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 43:

This table discloses the 132 compounds T43.001 to T43.132 of the formulaIa, wherein R is hydrogen, A is cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 44:

This table discloses the 132 compounds T44.001 to T44.132 of the formulaIa, wherein R is hydrogen, A is CH₂-cyclopropyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 45:

This table discloses the 132 compounds T45.001 to T45.132 of the formulaIa, wherein R is hydrogen, A is CH₂OCH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 46:

This table discloses the 132 compounds T46.001 to T46.132 of the formulaIa, wherein R is hydrogen, A is CH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 47:

This table discloses the 132 compounds T47.001 to T47.132 of the formulaIa, wherein R is hydrogen, A is CH₂OCH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 48:

This table discloses the 132 compounds T48.001 to T48.132 of the formulaIa, wherein R is hydrogen, A is CH₂CH₂OCH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 49:

This table discloses the 132 compounds T49.001 to T49.132 of the formulaIa, wherein R is hydrogen, A is oxetan-3-yl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 50:

This table discloses the 132 compounds T50.001 to T50.132 of the formulaIa, wherein R is hydrogen, A is CH₂CHF₂, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 51:

This table discloses the 132 compounds T51.001 to T51.132 of the formulaIa, wherein R is hydrogen, A is CH₂CF₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 52:

This table discloses the 132 compounds T52.001 to T52.132 of the formulaIa, wherein R is hydrogen, A is benzyl, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 53:

This table discloses the 132 compounds T53.001 to T53.132 of the formulaIa, wherein R is CH₂CH₃, A is CH₃, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 54:

This table discloses the 132 compounds T54.001 to T54.132 of the formulaIa, wherein R is CH₂CH₃, A is CH₂CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 55:

This table discloses the 132 compounds T55.001 to T55.132 of the formulaIa, wherein R is CH₂CH₃, A is i-C₃H₇, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 56:

This table discloses the 132 compounds T56.001 to T56.132 of the formulaIa, wherein R is CH₂CH₃, A is cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 57:

This table discloses the 132 compounds T57.001 to T57.132 of the formulaIa, wherein R is CH₂CH₃, A is CH₂-cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 58:

This table discloses the 132 compounds T58.001 to T58.132 of the formulaIa, wherein R is CH₂CH₃, A is CH₂OCH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 59:

This table discloses the 132 compounds T59.001 to T59.132 of the formulaIa, wherein R is CH₂CH₃, A is CH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 60:

This table discloses the 132 compounds T60.001 to T60.132 of the formulaIa, wherein R is CH₂CH₃, A is CH₂OCH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 61:

This table discloses the 132 compounds T61.001 to T61.132 of the formulaIa, wherein R is CH₂CH₃, A is CH₂CH₂OCH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 62:

This table discloses the 132 compounds T62.001 to T62.132 of the formulaIa, wherein R is CH₂CH₃, A is oxetan-3-yl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 63:

This table discloses the 132 compounds T63.001 to T63.132 of the formulaIa, wherein R is CH₂CH₃, A is CH₂CHF₂, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 64:

This table discloses the 132 compounds T64.001 to T64.132 of the formulaIa, wherein R is CH₂CH₃, A is CH₂CF₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 65:

This table discloses the 132 compounds T65.001 to T65.132 of the formulaIa, wherein R is CH₂CH₃, A is benzyl, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 66:

This table discloses the 132 compounds T66.001 to T66.132 of the formulaIa, wherein R is CH₂OCH₃, A is CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 67:

This table discloses the 132 compounds T67.001 to T67.132 of the formulaIa, wherein R is CH₂OCH₃, A is CH₂CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 68:

This table discloses the 132 compounds T68.001 to T68.132 of the formulaIa, wherein R is CH₂OCH₃, A is i-C₃H₇, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 69:

This table discloses the 132 compounds T69.001 to T69.132 of the formulaIa, wherein R is CH₂OCH₃, A is cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 70:

This table discloses the 132 compounds T70.001 to T70.132 of the formulaIa, wherein R is CH₂OCH₃, A is CH₂-cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 71:

This table discloses the 132 compounds T71.001 to T71.132 of the formulaIa, wherein R is CH₂OCH₃, A is CH₂OCH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 72:

This table discloses the 132 compounds T72.001 to T72.132 of the formulaIa, wherein R is CH₂OCH₃, A is CH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 73:

This table discloses the 132 compounds T73.001 to T73.132 of the formulaIa, wherein R is CH₂OCH₃, A is CH₂OCH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 74:

This table discloses the 132 compounds T74.001 to T74.132 of the formulaIa, wherein R is CH₂OCH₃, A is CH₂CH₂OCH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 75:

This table discloses the 132 compounds T75.001 to T75.132 of the formulaIa, wherein R is CH₂OCH₃, A is oxetan-3-yl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 76:

This table discloses the 132 compounds T76.001 to T76.132 of the formulaIa, wherein R is CH₂OCH₃, A is CH₂CHF₂, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 77:

This table discloses the 132 compounds T77.001 to T77.132 of the formulaIa, wherein R is CH₂OCH₃, A is CH₂CF₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 78:

This table discloses the 132 compounds T78.001 to T78.132 of the formulaIa, wherein R is CH₂OCH₃, A is benzyl, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 79:

This table discloses the 132 compounds T79.001 to T79.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 80:

This table discloses the 132 compounds T80.001 to T80.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is CH₂CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 81:

This table discloses the 132 compounds T81.001 to T81.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is i-C₃H₇, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 82:

This table discloses the 132 compounds T82.001 to T82.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 83:

This table discloses the 132 compounds T83.001 to T83.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is CH₂-cyclopropyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 84:

This table discloses the 132 compounds T84.001 to T84.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 85:

This table discloses the 132 compounds T85.001 to T85.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is CH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 86:

This table discloses the 132 compounds T86.001 to T86.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is CH₂OCH₂CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 87:

This table discloses the 132 compounds T87.001 to T87.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is CH₂CH₂OCH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 88:

This table discloses the 132 compounds T88.001 to T88.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is oxetan-3-yl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 89:

This table discloses the 132 compounds T89.001 to T89.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is CH₂CHF₂, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 90:

This table discloses the 132 compounds T90.001 to T90.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is CH₂CF₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 91:

This table discloses the 132 compounds T91.001 to T91.132 of the formulaIa, wherein R is CH₂CH₂OCH₃, A is benzyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 92:

This table discloses the 132 compounds T92.001 to T92.132 of the formulaIa, wherein R is benzyl, A is CH₃, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined in Table 1.

Table 93:

This table discloses the 132 compounds T93.001 to T93.132 of the formulaIa, wherein R is benzyl, A is CH₂CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 94:

This table discloses the 132 compounds T94.001 to T94.132 of the formulaIa, wherein R is benzyl, A is i-C₃H₇, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 95:

This table discloses the 132 compounds T95.001 to T95.132 of the formulaIa, wherein R is benzyl, A is cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 96:

This table discloses the 132 compounds T96.001 to T96.132 of the formulaIa, wherein R is benzyl, A is CH₂-cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 97:

This table discloses the 132 compounds T97.001 to T97.132 of the formulaIa, wherein R is benzyl, A is CH₂OCH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 98:

This table discloses the 132 compounds T98.001 to T98.132 of the formulaIa, wherein R is benzyl, A is CH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 99:

This table discloses the 132 compounds T99.001 to T99.132 of the formulaIa, wherein R is benzyl, A is CH₂OCH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 100:

This table discloses the 132 compounds T100.001 to T100.132 of theformula Ia, wherein R is benzyl, A is CH₂CH₂OCH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 101:

This table discloses the 132 compounds T101.001 to T101.132 of theformula Ia, wherein R is benzyl, A is oxetan-3-yl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 102:

This table discloses the 132 compounds T102.001 to T102.132 of theformula Ia, wherein R is benzyl, A is CH₂CHF₂, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 103:

This table discloses the 132 compounds T103.001 to T103.132 of theformula Ia, wherein R is benzyl, A is CH₂CF₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 104:

This table discloses the 132 compounds T104.001 to T104.132 of theformula Ia, wherein R is benzyl, A is benzyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 105:

This table discloses the 132 compounds T105.001 to T105.132 of theformula Ia, wherein R is CH₃, A is methoxypropyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 106:

This table discloses the 132 compounds T106.001 to T106.132 of theformula Ia, wherein R is CH₃, A is oxetan-3-ylmethyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 107:

This table discloses the 132 compounds T107.001 to T107.132 of theformula Ia, wherein R is CH₃, A is tetrahydrofuran-2-ylmethyl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 108:

This table discloses the 132 compounds T108.001 to T108.132 of theformula Ia, wherein R is CH₃, A is tetrahydrofuran-3-ylmethyl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 109:

This table discloses the 132 compounds T109.001 to T109.132 of theformula Ia, wherein R is CH₃, A is tetrahydropyran-4-ylmethyl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 110:

This table discloses the 132 compounds T110.001 to T110.132 of theformula Ia, wherein R is CH₃, A is methylthioethyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 111:

This table discloses the 132 compounds T111.001 to T111.132 of theformula Ia, wherein R is H, A is methoxypropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 112:

This table discloses the 132 compounds T112.001 to T112.132 of theformula Ia, wherein R is CH₂CH₃, A is methoxypropyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 113:

This table discloses the 132 compounds T113.001 to T113.132 of theformula Ia, wherein R is CH₂CH₂OCH₃, A is methoxypropyl, G is hydrogenand R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 114:

This table discloses the 132 compounds T114.001 to T114.132 of theformula Ia, wherein R is H, A is tetrahydrofuran-2-ylmethyl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 115:

This table discloses the 132 compounds T115.001 to T115.132 of theformula Ia, wherein R is CH₂CH₃, A is tetrahydrofuran-2-ylmethyl, G ishydrogen and R_(a), R_(b), R_(c) and

R_(d) are as defined in Table 1.

Table 116:

This table discloses the 132 compounds T116.001 to T116.132 of theformula Ia, wherein R is CH₂CH₂OCH₃, A is tetrahydrofuran-2-ylmethyl, Gis hydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

TABLE 1ii This table discloses the 132 compounds T1ii.001 to T1ii.132 ofthe formula Ib: (Ib)

wherein R is CH₃, A is hydrogen, G is hydrogen and R_(a), R_(b), R_(c)and R_(d) are as defined below: No. R_(a) R_(b) R_(c) R_(d) T1ii.001 BrH H H Tlii.002 Cl H H H T1ii.003 CH₃ H H H T1ii.004 CH₂CH₃ H H HT1ii.005 OCH₃ H H H T1ii.006 Br Cl H H T1ii.007 Cl Br H H T1ii.008 Cl ClH H T1ii.009 Cl CH₃ H H T1ii.010 CH₃ Cl H H T1ii.011 CH₃ CH₃ H HT1ii.012 Cl H Cl H T1ii.013 Cl H CH₃ H T1ii.014 Cl H CH₂CH₃ H T1ii.015Cl H OCH₃ H T1ii.016 CH₃ H CH₃ H T1ii.017 CH₃ H CH₂CH₃ H T1ii.018 CH₃ HOCH₃ H T1ii.019 CH₂CH₃ H CH₂CH₃ H T1ii.020 CH₂CH₃ H OCH₃ H T1ii.021 OCH₃H OCH₃ H T1ii.022 Br H H Cl T1ii.023 Br H H CH₃ T1ii.024 Br H H4-Cl-C₆H₄ T1ii.025 Cl H H Cl T1ii.026 Cl H H CH₃ T1ii.027 Cl H H4-Cl-C₆H₄ T1ii.028 CH₃ H H Br T1ii.029 CH₃ H H Cl T1ii.030 CH₃ H H CH₃T1ii.031 CH₃ H H C₆H₅ T1ii.032 CH₃ H H 4-Cl-C₆H₄ T1ii.033 CH₂CH₃ H H CH₃T1ii.034 CH₂CH₃ H H 4-Cl-C₆H₄ T1ii.035 OCH₃ H H CH₃ T1ii.036 OCH₃ H H4-Cl-C₆H₄ T1ii.037 Cl H Cl Br T1ii.038 CH₃ H CH₃ Br T1ii.039 CH₃ H CH₃Cl T1ii.040 CH₃ H CH₃ 4-Cl-C₆H₄ T1ii.041 Br Cl H CH₃ T1ii.042 Br CH₃ HCH₃ T1ii.043 Cl Cl H Cl T1ii.044 Cl Br H CH₃ T1ii.045 Cl Cl H CH₃T1ii.046 Cl CH₃ H Cl T1ii.047 Cl CH₃ H CH₃ T1ii.048 CH₃ Br H CH₃T1ii.049 CH₃ Cl H CH₃ T1ii.050 CH₃ CH₃ H CH₃ T1ii.051 CH₃ CH₃ H4-Cl-C₆H₄ T1ii.052 Br Br CH₃ H T1ii.053 Br Cl CH₃ H T1ii.054 Br CH₃ Br HT1ii.055 Br CH₃ Cl H T1ii.056 Cl Br CH₃ H T1ii.057 Cl Cl Cl H T1ii.058Cl Cl CH₃ H T1ii.059 Cl CH₃ Cl H T1ii.060 Cl CH₃ CH₂CH₃ H T1ii.061 ClCH₃ OCH₃ H T1ii.062 Cl 4-Cl-C₆H₄ Cl H T1ii.063 Cl 4-Cl-C₆H₄ CH₃ HT1ii.064 Cl 4-Cl-C₆H₄ CH₂CH₃ H T1ii.065 Cl 4-Cl-C₆H₄ OCH₃ H T1ii.066 CH₃Br CH₃ H T1ii.067 CH₃ Cl CH₃ H T1ii.068 CH₃ CH₃ Br H T1ii.069 CH₃ CH₃ ClH T1ii.070 CH₃ CH₃ CH₃ H T1ii.071 CH₃ CH₃ CH₂CH₃ H T1ii.072 CH₃ CH₃ OCH₃H T1ii.073 CH₃ 4-Cl-C₆H₄ CH₃ H T1ii.074 CH₃ 4-Cl-C₆H₄ CH₂CH₃ H T1ii.075CH₃ 4-Cl-C₆H₄ OCH₃ H T1ii.076 CH₂CH₃ Br Br H T1ii.077 CH₂CH₃ Br Cl HT1ii.078 CH₂CH₃ Br CH₃ H T1ii.079 CH₂CH₃ Br CH₂CH₃ H T1ii.080 CH₂CH₃ BrOCH₃ H T1ii.081 CH₂CH₃ Cl Br H T1ii.082 CH₂CH₃ Cl Cl H T1ii.083 CH₂CH₃Cl CH₃ H T1ii.084 CH₂CH₃ Cl CH₂CH₃ H T1ii.085 CH₂CH₃ Cl OCH₃ H T1ii.086CH₂CH₃ CH₃ Br H T1ii.087 CH₂CH₃ CH₃ Cl H T1ii.088 CH₂CH₃ CH₃ CH₂CH₃ HT1ii.089 CH₂CH₃ CH₃ OCH₃ H T1ii.090 CH₂CH₃ CH₂CH₃ CH₃ H T1ii.091 CH₂CH₃CH₂CH₃ CH₂CH₃ H T1ii.092 CH₂CH₃ 4-Cl-C₆H₄ Br H T1ii.093 CH₂CH₃ 4-Cl-C₆H₄CH₂CH₃ H T1ii.094 CH₂CH₃ 4-Cl-C₆H₄ OCH₃ H T1ii.095 OCH₃ Br CH₃ HT1ii.096 OCH₃ Cl CH₃ H T1ii.097 OCH₃ CH₃ Br H T1ii.098 OCH₃ CH₃ Cl HT1ii.099 OCH₃ CH₃ OCH₃ H T1ii.100 OCH₃ 4-Cl-C₆H₄ OCH₃ H T1ii.101 CH₃ CH₃CH₃ F T1ii.102 CH₃ CH₃ CH₃ Cl T1ii.103 CH₃ CH₃ CH₃ Br T1ii.104 CH₃ CH₃CH₃ CH₃ T1ii.105 CH₃ CH₃ CH₃ 4-Cl-C₆H₄ T1ii.106 Cl CH₃ CH₃ CH₃ T1ii.107CH₃ Cl CH₃ CH₃ T1ii.108 CH₃ CH₃ Cl CH₃ T1ii.109 CH₂CH₃ CH₃ CH₃ CH₃T1ii.110 OCH₃ CH₃ CH₃ CH₃ T1ii.111 Cyclo-C3 CH₃ CH₃ CH₃ T1ii.112 CH₃ CH₃Cyclo-C3 H T1ii.113 CH₃ F H Br T1ii.114 CH₃ CH₃ H Br T1ii.115 CH₂CH₃ CH₃H CH₃ T1ii.116 OCH₃ CH₃ H CH₃ T1ii.117 Cyclo-C3 CH₃ H CH₃ T1ii.118CH₂CH₃ Cl H CH₃ T1ii.119 OCH₃ Cl H CH₃ T1ii.120 Cyclo-C3 Cl H CH₃T1ii.121 Cl H CH₃ CH₃ T1ii.122 CH₃ H CH₃ CH₃ T1ii.123 CH₂CH₃ H CH₃ CH₃T1ii.124 OCH₃ H CH₃ CH₃ T1ii.125 Cyclo-C3 H CH₃ CH₃ T1ii.126 F H Cl CH₃T1ii.127 Cl H F CH₃ T1ii.128 H CH₃ CH₃ CH₃ T1ii.129 Br CH₃ CH₃ CH₃T1ii.130 CH₃ H Cl CH₃ T1ii.131 CH₃ H Br CH₃ T1ii.132 Br H CH₃ CH₃Cyclo-C3 means cyclopropyl.

Table 2ii:

This table discloses the 132 compounds T2ii.001 to T2ii.132 of theformula Ib, wherein R is CH₃, A is CH₃, G is hydrogen and R_(a), R_(b),R_(c) and R_(d) are as defined in Table 1.

Table 3ii:

This table discloses the 132 compounds T3ii.001 to T3ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 4ii:

This table discloses the 132 compounds T4ii.001 to T4ii.132 of theformula Ib, wherein R is CH₃, A is n-C₃H₇, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 5ii:

This table discloses the 132 compounds T5ii.001 to T5ii.132 of theformula Ib, wherein R is CH₃, A is i-C₃H₇, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 6ii:

This table discloses the 132 compounds T6ii.001 to T6ii.132 of theformula Ib, wherein R is CH₃, A is n-C₄H₉, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 7ii:

This table discloses the 132 compounds T7ii.001 to T7ii.132 of theformula Ib, wherein R is CH₃, A is i-C₄H₉, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 8ii:

This table discloses the 132 compounds T8ii.001 to T8ii.132 of theformula Ib, wherein R is CH₃, A is t-C₄H₉, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 9ii:

This table discloses the 132 compounds T9ii.001 to T9ii.132 of theformula Ib, wherein R is CH₃, A is cyclopropyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 10ii:

This table discloses the 132 compounds T10ii.001 to T10ii.132 of theformula Ib, wherein R is CH₃, A is cyclopentyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 11ii:

This table discloses the 132 compounds T11ii.001 to T11ii.132 of theformula Ib, wherein R is CH₃, A is cyclohexyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 12ii:

This table discloses the 132 compounds T12ii.001 to T12ii.132 of theformula Ib, wherein R is CH₃, A is 2,2-(CH₃)₂-propyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 13ii:

This table discloses the 132 compounds T13ii.001 to T13ii.132 of theformula Ib, wherein R is CH₃, A is allyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 14ii:

This table discloses the 132 compounds T14ii.001 to T14ii.132 of theformula Ib, wherein R is CH₃, A is CH₂—CH═C(CH₃)₂, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 15ii:

This table discloses the 132 compounds T15ii.001 to T15ii.132 of theformula Ib, wherein R is CH₃, A is CH₂—CH═C(Cl)₂, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 16ii:

This table discloses the 132 compounds T16ii.001 to T16ii.132 of theformula Ib, wherein R is CH₃, A is propargyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 17ii:

This table discloses the 132 compounds T17ii.001 to T17ii.132 of theformula Ib, wherein R is CH₃, A is CH₂C≡CCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 18ii:

This table discloses the 132 compounds T18ii.001 to T18ii.132 of theformula Ib, wherein R is CH₃, A is CH₂-cyclopropyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 19ii:

This table discloses the 132 compounds T19ii.001 to T19ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CN, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 20ii:

This table discloses the 132 compounds T20ii.001 to T20ii.132 of theformula Ib, wherein R is CH₃, A is CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 21ii:

This table discloses the 132 compounds T21ii.001 to T21ii.132 of theformula Ib, wherein R is CH₃, A is CH₂OCH₂CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 22ii:

This table discloses the 132 compounds T22ii.001 to T22ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 23ii:

This table discloses the 132 compounds T23ii.001 to T23ii.132 of theformula Ib, wherein R is CH₃, A is CH₂OCH₂CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 24ii:

This table discloses the 132 compounds T24ii.001 to T24ii.132 of theformula Ib, wherein R is CH₃, A is oxetan-3-yl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 25ii:

This table discloses the 132 compounds T25ii.001 to T25ii.132 of theformula Ib, wherein R is CH₃, A is tetrahydrofuran-2-yl, G is hydrogenand R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 26ii:

This table discloses the 132 compounds T26ii.001 to T26ii.132 of theformula Ib, wherein R is CH₃, A is tetrahydrofuran-3-yl, G is hydrogenand R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 27ii:

This table discloses the 132 compounds T27ii.001 to T27ii.132 of theformula Ib, wherein R is CH₃, A is tetrahydropyran-2-yl, G is hydrogenand R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 28ii:

This table discloses the 132 compounds T28ii.001 to T28ii.132 of theformula Ib, wherein R is CH₃, A is tetrahydropyran-4-yl, G is hydrogenand R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 29ii:

This table discloses the 132 compounds T29ii.001 to T29ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CHF₂, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 30ii:

This table discloses the 132 compounds T30ii.001 to T30ii.132 of theformula Ib, wherein R is CH₃, A is CH₂C(O)—CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 31ii:

This table discloses the 132 compounds T31ii.001 to T31ii.132 of theformula Ib, wherein R is CH₃, A is CH₂C(O)—CH₂CH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 32ii:

This table discloses the 132 compounds T32ii.001 to T32ii.132 of theformula Ib, wherein R is CH₃, A is CH(CH₃)C(O)—CH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 33ii:

This table discloses the 132 compounds T33ii.001 to T33ii.132 of theformula Ib, wherein R is CH₃, A is C(CH₃)₂C(O)—CH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 34ii:

This table discloses the 132 compounds T34ii.001 to T34ii.132 of theformula Ib, wherein R is CH₃, A is benzyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 35ii:

This table discloses the 132 compounds T35ii.001 to T35ii.132 of theformula Ib, wherein R is CH₃, A is C(O)—CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 36ii:

This table discloses the 132 compounds T36ii.001 to T36ii.132 of theformula Ib, wherein R is CH₃, A is C(O)—OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 37ii:

This table discloses the 132 compounds T37ii.001 to T37ii.132 of theformula Ib, wherein R is CH₃, A is C(O)-cyclopropyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 38ii:

This table discloses the 132 compounds T37ii.001 to T37ii.132 of theformula Ib, wherein R is CH₃, A is C(O)—N(CH₃)₂, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 39ii:

This table discloses the 132 compounds T39ii.001 to T39ii.132 of theformula Ib, wherein R is hydrogen, A is hydrogen, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 40ii:

This table discloses the 132 compounds T40ii.001 to T40ii.132 of theformula Ib, wherein R is hydrogen, A is CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 41ii:

This table discloses the 132 compounds T41ii.001 to T41ii.132 of theformula Ib, wherein R is hydrogen, A is CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 42ii:

This table discloses the 132 compounds T42ii.001 to T42ii.132 of theformula Ib, wherein R is hydrogen, A is CH₂CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 43ii:

This table discloses the 132 compounds T43ii.001 to T43ii.132 of theformula Ib, wherein R is hydrogen, A is propargyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 44ii:

This table discloses the 132 compounds T44ii.001 to T44ii.132 of theformula Ib, wherein R is CH₂CH₃, A is hydrogen, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 45ii:

This table discloses the 132 compounds T45ii.001 to T45ii.132 of theformula Ib, wherein R is CH₂CH₃, A is CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 46ii:

This table discloses the 132 compounds T46ii.001 to T46ii.132 of theformula Ib, wherein R is CH₂CH₃, A is CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 47ii:

This table discloses the 132 compounds T47ii.001 to T47ii.132 of theformula Ib, wherein R is CH₂CH₃, A is CH₂CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 48ii:

This table discloses the 132 compounds T48ii.001 to T48ii.132 of theformula Ib, wherein R is CH₂CH₃, A is propargyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 49ii:

This table discloses the 132 compounds T49ii.001 to T49ii.132 of theformula Ib, wherein R is CH₂OCH₃, A is hydrogen, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 50ii:

This table discloses the 132 compounds T50ii.001 to T50ii.132 of theformula Ib, wherein R is CH₂OCH₃, A is CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 51 ii:

This table discloses the 132 compounds T51ii.001 to T51ii.132 of theformula Ib, wherein R is CH₂OCH₃, A is CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 52ii:

This table discloses the 132 compounds T52ii.001 to T52ii.132 of theformula Ib, wherein R is CH₂OCH₃, A is CH₂CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 53ii:

This table discloses the 132 compounds T53ii.001 to T53ii.132 of theformula Ib, wherein R is CH₂OCH₃, A is propargyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 54ii:

This table discloses the 132 compounds T54ii.001 to T54ii.132 of theformula Ib, wherein R is CH₂CH₂OCH₃, A is hydrogen, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 55ii:

This table discloses the 132 compounds T55ii.001 to T55ii.132 of theformula Ib, wherein R is CH₂CH₂OCH₃, A is CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 56ii:

This table discloses the 132 compounds T56ii.001 to T56ii.132 of theformula Ib, wherein R is CH₂CH₂OCH₃, A is CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 57ii:

This table discloses the 132 compounds T57ii.001 to T57ii.132 of theformula Ib, wherein R is CH₂CH₂OCH₃, A is CH₂CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 58ii:

This table discloses the 132 compounds T58ii.001 to T58ii.132 of theformula Ib, wherein R is CH₂CH₂OCH₃, A is propargyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 59ii:

This table discloses the 132 compounds T59ii.001 to T59ii.132 of theformula Ib, wherein R is benzyl, A is hydrogen, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 60ii:

This table discloses the 132 compounds T60ii.001 to T60ii.132 of theformula Ib, wherein R is benzyl, A is CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 61 ii:

This table discloses the 132 compounds T61ii.001 to T61ii.132 of theformula Ib, wherein R is benzyl, A is CH₂OCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 62ii:

This table discloses the 132 compounds T62ii.001 to T62ii.132 of theformula Ib, wherein R is benzyl, A is CH₂CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 63ii:

This table discloses the 132 compounds T63ii.001 to T63ii.132 of theformula Ib, wherein R is benzyl, A is propargyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 64ii:

This table discloses the 132 compounds T64ii.001 to T64ii.132 of theformula Ib, wherein R is CH₃, A is cyclobutyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 65ii:

This table discloses the 132 compounds T65ii.001 to T65ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CH₂CH₂OCH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 66ii:

This table discloses the 132 compounds T66ii.001 to T66ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CH₂O(tetrahydrofuran-2-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 67ii:

This table discloses the 132 compounds T67ii.001 to T67ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CH₂O(tetrahydropyran-2-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 68ii:

This table discloses the 132 compounds T68ii.001 to T68ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(oxetan-3-yl), G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 69ii:

This table discloses the 132 compounds T69ii.001 to T69ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(3-methyl-oxetan-3-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 70ii:

This table discloses the 132 compounds T70ii.001 to T70ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(tetrahydrofuran-2-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 71 ii:

This table discloses the 132 compounds T71 ii.001 to T71ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(tetrahydrofuran-3-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 72ii:

This table discloses the 132 compounds T72ii.001 to T72ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(tetrahydropyran-2-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 73ii:

This table discloses the 132 compounds T73ii.001 to T73ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(tetrahydropyran-3-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 74ii:

This table discloses the 132 compounds T74ii.001 to T74ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(tetrahydropyran-4-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 75ii:

This table discloses the 132 compounds T75ii.001 to T75ii.132 of theformula Ib, wherein R is hydrogen, A is CH₂CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 76ii:

This table discloses the 132 compounds T76ii.001 to T76ii.132 of theformula Ib, wherein R is hydrogen, A is allyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 77ii:

This table discloses the 132 compounds T77ii.001 to T77ii.132 of theformula Ib, wherein R is hydrogen, A is tetrahydrofuran-2-yl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 78ii:

This table discloses the 132 compounds T78ii.001 to T78ii.132 of theformula Ib, wherein R is hydrogen, A is tetrahydropyran-2-yl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 79ii:

This table discloses the 132 compounds T79ii.001 to T79ii.132 of theformula Ib, wherein R is CH₂CH₃, A is CH₂CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 80ii:

This table discloses the 132 compounds T80ii.001 to T80ii.132 of theformula Ib, wherein R is CH₂CH₃, A is allyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 81ii:

This table discloses the 132 compounds T81ii.001 to T81ii.132 of theformula Ib, wherein R is CH₂CH₃, A is tetrahydrofuran-2-yl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 82ii:

This table discloses the 132 compounds T82ii.001 to T82ii.132 of theformula Ib, wherein R is CH₂CH₃, A is tetrahydropyran-2-yl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 83ii:

This table discloses the 132 compounds T83ii.001 to T83ii.132 of theformula Ib, wherein R is CH₂OCH₃, A is CH₂CH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 84ii:

This table discloses the 132 compounds T84ii.001 to T84ii.132 of theformula Ib, wherein R is CH₂OCH₃, A is allyl, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 85ii:

This table discloses the 132 compounds T85ii.001 to T85ii.132 of theformula Ib, wherein R is CH₂OCH₃, A is tetrahydrofuran-2-yl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 86ii:

This table discloses the 132 compounds T86ii.001 to T86ii.132 of theformula Ib, wherein R is CH₂OCH₃, A is tetrahydropyran-2-yl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 87ii:

This table discloses the 132 compounds T87ii.001 to T87ii.132 of theformula Ib, wherein R is CH₂CH₂OCH₃, A is CH₂CH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 88ii:

This table discloses the 132 compounds T88ii.001 to T88ii.132 of theformula Ib, wherein R is CH₂CH₂OCH₃, A is allyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 89ii:

This table discloses the 132 compounds T89ii.001 to T89ii.132 of theformula Ib, wherein R is CH₂CH₂OCH₃, A is tetrahydrofuran-2-yl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 90ii:

This table discloses the 132 compounds T90ii.001 to T90ii.132 of theformula Ib, wherein R is CH₂CH₂OCH₃, A is tetrahydropyran-2-yl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 91ii:

This table discloses the 132 compounds T91ii.001 to T91ii.132 of theformula Ib, wherein R is CH₃, A is CH₂-cyclobutyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 92ii:

This table discloses the 132 compounds T92ii.001 to T92ii.132 of theformula Ib, wherein R is CH₃, A is CH₂-cyclopentyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 93ii:

This table discloses the 132 compounds T93ii.001 to T93ii.132 of theformula Ib, wherein R is CH₃, A is CH₂-cyclohexyl, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 94ii:

This table discloses the 132 compounds T94ii.001 to T94ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(3-ethyl-oxetan-3-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 95ii:

This table discloses the 132 compounds T95ii.001 to T95ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(furan-2-yl), G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 96ii:

This table discloses the 132 compounds T96ii.001 to T96ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(furan-3-yl), G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 97ii:

This table discloses the 132 compounds T97ii.001 to T97ii.132 of theformula Ib, wherein R is CH₃, A is CH₂(tetrahydro-thiopyran-4-yl), G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 98ii:

This table discloses the 132 compounds T98ii.001 to T98ii.132 of theformula Ib, wherein R is CH₃, A is C(O)—OCH₂CH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 99ii:

This table discloses the 132 compounds T99ii.001 to T99ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CH₂SCH₃, G is hydrogen and R_(a),R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 100ii:

This table discloses the 132 compounds T100ii.001 to T100ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CH₂S(O)CH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 101ii:

This table discloses the 132 compounds T101ii.001 to T101ii.132 of theformula Ib, wherein R is CH₃, A is CH₂CH₂S(O)₂CH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 102ii:

This table discloses the 132 compounds T102ii.001 to T102ii.132 of theformula Ib, wherein R is CH₃, A is 1-methoxy-piperidin-4-yl, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

TABLE 1iii This table discloses the 105 compounds T1iii.001 to T1iii.105of the formula Ic: (Ic)

wherein R is CH₃, R₁, R₂, R₃ and R₄ are hydrogen, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined below: No. R_(a) R_(b)R_(c) R_(d) T1iii.001 Br H H H T1iii.002 Cl H H H T1iii.003 CH₃ H H HT1iii.004 CH₂CH₃ H H H T1iii.005 OCH₃ H H H T1iii.006 Br Cl H HT1iii.007 Cl Br H H T1iii.008 Cl Cl H H T1iii.009 Cl CH₃ H H T1iii.010CH₃ Cl H H T1iii.011 CH₃ CH₃ H H T1iii.012 Cl H Cl H T1iii.013 Cl H CH₃H T1iii.014 Cl H CH₂CH₃ H T1iii.015 Cl H OCH₃ H T1iii.016 CH₃ H CH₃ HT1iii.017 CH₃ H CH₂CH₃ H T1iii.018 CH₃ H OCH₃ H T1iii.019 CH₂CH₃ HCH₂CH₃ H T1iii.020 CH₂CH₃ H OCH₃ H T1iii.021 OCH₃ H OCH₃ H T1iii.022 BrH H Cl T1iii.023 Br H H CH₃ T1iii.024 Br H H 4-Cl-C₆H₄ T1iii.025 Cl H HCl T1iii.026 Cl H H CH₃ T1iii.027 Cl H H 4-Cl-C₆H₄ T1iii.028 CH₃ H H BrT1iii.029 CH₃ H H Cl T1iii.030 CH₃ H H CH₃ T1iii.031 CH₃ H H C₆H₅T1iii.032 CH₃ H H 4-Cl-C₆H₄ T1iii.033 CH₂CH₃ H H CH₃ T1iii.034 CH₂CH₃ HH 4-Cl-C₆H₄ T1iii.035 OCH₃ H H CH₃ T1iii.036 OCH₃ H H 4-Cl-C₆H₄T1iii.037 Cl H Cl Br T1iii.038 CH₃ H CH₃ Br T1iii.039 CH₃ H CH₃ ClT1iii.040 CH₃ H CH₃ 4-Cl-C₆H₄ T1iii.041 Br Cl H CH₃ T1iii.042 Br CH₃ HCH₃ T1iii.043 Cl Cl H Cl T1iii.044 Cl Br H CH₃ T1iii.045 Cl Cl H CH₃T1iii.046 Cl CH₃ H Cl T1iii.047 Cl CH₃ H CH₃ T1iii.048 CH₃ Br H CH₃T1iii.049 CH₃ Cl H CH₃ T1iii.050 CH₃ CH₃ H CH₃ T1iii.051 CH₃ CH₃ H4-Cl-C₆H₄ T1iii.052 Br Br CH₃ H T1iii.053 Br Cl CH₃ H T1iii.054 Br CH₃Br H T1iii.055 Br CH₃ Cl H T1iii.056 Cl Br CH₃ H T1iii.057 Cl Cl Cl HT1iii.058 Cl Cl CH₃ H T1iii.059 Cl CH₃ Cl H T1iii.060 Cl CH₃ CH₂CH₃ HT1iii.061 Cl CH₃ OCH₃ H T1iii.062 Cl 4-Cl-C₆H₄ Cl H T1iii.063 Cl4-Cl-C₆H₄ CH₃ H T1iii.064 Cl 4-Cl-C₆H₄ CH₂CH₃ H T1iii.065 Cl 4-Cl-C₆H₄OCH₃ H T1iii.066 CH₃ Br CH₃ H T1iii.067 CH₃ Cl CH₃ H T1iii.068 CH₃ CH₃Br H T1iii.069 CH₃ CH₃ Cl H T1iii.070 CH₃ CH₃ CH₃ H T1iii.071 CH₃ CH₃CH₂CH₃ H T1iii.072 CH₃ CH₃ OCH₃ H T1iii.073 CH₃ 4-Cl-C₆H₄ CH₃ HT1iii.074 CH₃ 4-Cl-C₆H₄ CH₂CH₃ H T1iii.075 CH₃ 4-Cl-C₆H₄ OCH₃ HT1iii.076 CH₂CH₃ Br Br H T1iii.077 CH₂CH₃ Br Cl H T1iii.078 CH₂CH₃ BrCH₃ H T1iii.079 CH₂CH₃ Br CH₂CH₃ H T1iii.080 CH₂CH₃ Br OCH₃ H T1iii.081CH₂CH₃ Cl Br H T1iii.082 CH₂CH₃ Cl Cl H T1iii.083 CH₂CH₃ Cl CH₃ HT1iii.084 CH₂CH₃ Cl CH₂CH₃ H T1iii.085 CH₂CH₃ Cl OCH₃ H T1iii.086 CH₂CH₃CH₃ Br H T1iii.087 CH₂CH₃ CH₃ Cl H T1iii.088 CH₂CH₃ CH₃ CH₂CH₃ HT1iii.089 CH₂CH₃ CH₃ OCH₃ H T1iii.090 CH₂CH₃ CH₂CH₃ CH₃ H T1iii.091CH₂CH₃ CH₂CH₃ CH₂CH₃ H T1iii.092 CH₂CH₃ 4-Cl-C₆H₄ Br H T1iii.093 CH₂CH₃4-Cl-C₆H₄ CH₂CH₃ H T1iii.094 CH₂CH₃ 4-Cl-C₆H₄ OCH₃ H T1iii.095 OCH₃ BrCH₃ H T1iii.096 OCH₃ Cl CH₃ H T1iii.097 OCH₃ CH₃ Br H T1iii.098 OCH₃ CH₃Cl H T1iii.099 OCH₃ CH₃ OCH₃ H T1iii.100 OCH₃ 4-Cl-C₆H₄ OCH₃ H T1iii.101CH₃ CH₃ CH₃ F T1iii.102 CH₃ CH₃ CH₃ Cl T1iii.103 CH₃ CH₃ CH₃ BrT1iii.104 CH₃ CH₃ CH₃ CH₃ T1iii.105 CH₃ CH₃ CH₃ 4-Cl-C₆H₄

Table 2iii:

This table discloses the 105 compounds T2iii.001 to T2iii.105 of theformula Ic, wherein R is CH₂CH₃, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 3iii:

This table discloses the 105 compounds T3iii.001 to T3iii.105 of theformula Ic, wherein R is n-C₃H₇, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 4iii:

This table discloses the 105 compounds T4iii.001 to T4iii.105 of theformula Ic, wherein R is i-C₃H₇, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 5iii:

This table discloses the 105 compounds T5iii.001 to T5iii.105 of theformula Ic, wherein R is allyl, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 6iii:

This table discloses the 105 compounds T6iii.001 to T6iii.105 of theformula Ic, wherein R is benzyl, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 7iii:

This table discloses the 105 compounds T7iii.001 to T7iii.105 of theformula Ic, wherein R is C(═O)—CH₃, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 8iii:

This table discloses the 105 compounds T8iii.001 to T8iii.105 of theformula Ic, wherein R is C(═O)—CH₂CH₃, R₁, R₂, R₃ and R₄ are hydrogen, Gis hydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 9iii:

This table discloses the 105 compounds T9iii.001 to T9iii.105 of theformula Ic, wherein R is C(═O)-n-C₃H₇, R₁, R₂, R₃ and R₄ are hydrogen, Gis hydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 10iii:

This table discloses the 105 compounds T10iii.001 to T10iii.105 of theformula Ic, wherein R is C(═O)O—CH₃, R₁, R₂, R₃ and R₄ are hydrogen, Gis hydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 11 iii:

This table discloses the 105 compounds T11iii.001 to T11iii.105 of theformula Ic, wherein R is C(═O)O—CH₂CH₃, R₁, R₂, R₃ and R₄ are hydrogen,G is hydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table1.

Table 12iii:

This table discloses the 105 compounds T12iii.001 to T12iii.105 of theformula Ic, wherein R is C(═O)O-n-C₃H₇, R₁, R₂, R₃ and R₄ are hydrogen,G is hydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table1.

Table 13iii:

This table discloses the 105 compounds T13iii.001 to T13iii.105 of theformula

Ic, wherein R is C(═O)NH—CH₃, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 14iii:

This table discloses the 105 compounds T14iii.001 to T14iii.105 of theformula Ic, wherein R is C(═O)NH—CH₂CH₃, R₁, R₂, R₃ and R₄ are hydrogen,G is hydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table1.

Table 15iii:

This table discloses the 105 compounds T15iii.001 to T15iii.105 of theformula Ic, wherein R is C(═O)NH-n-C₃H₇, R₁, R₂, R₃ and R₄ are hydrogen,G is hydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table1.

Table 16iii:

This table discloses the 105 compounds T16iii.001 to T16iii.105 of theformula Ic, wherein R is hydrogen, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 17iii:

This table discloses the 105 compounds T17iii.001 to T17iii.105 of theformula Ic, wherein R is CH₂—O—CH₃, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 18iii:

This table discloses the 105 compounds T18iii.001 to T18iii.105 of theformula

Ic, wherein R is CH₂—O—C₂H₅, R₁, R₂, R₃ and R₄ are hydrogen, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 19iii:

This table discloses the 105 compounds T19iii.001 to T19iii.105 of theformula Ic, wherein R is CH₂—O—C₂H₄—O—CH₃, R₁, R₂, R₃ and R₄ arehydrogen, G is hydrogen and R_(a), R_(b), R_(c) and R_(d) are as definedin Table 1.

Table 20iii:

This table discloses the 105 compounds T20iii.001 to T20iii.105 of theformula Ic, wherein R is hydrogen, R₁, R₂, R₃ and R₄ are CH₃, G ishydrogen and R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 21 iii:

This table discloses the 105 compounds T21 iii.001 to T21iii.105 of theformula Ic, wherein R is CH₃, R₁, R₂, R₃ and R₄ are CH₃, G is hydrogenand R_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Table 22iii:

This table discloses the 105 compounds T22iii.001 to T22iii.105 of theformula

Ic, wherein R is C₂H₅, R₁, R₂, R₃ and R₄ are CH₃, G is hydrogen andR_(a), R_(b), R_(c) and R_(d) are as defined in Table 1.

Pest control may be achieved in a range of crops. Suitable target cropsare, in particular, cereals, such as wheat, barley, rye, oats, rice,maize or sorghum; beet, such as sugar or fodder beet; fruit, for examplepomaceous fruit, stone fruit or soft fruit, such as apples, pears,plums, peaches, almonds, cherries or berries, for example strawberries,raspberries or blackberries; leguminous crops, such as beans, lentils,peas or soya; oil crops, such as oilseed rape, mustard, poppies, olives,sunflowers, coconut, castor, cocoa or ground nuts; cucurbits, such aspumpkins, cucumbers or melons; fibre plants, such as cotton, flax, hempor jute; citrus fruit, such as oranges, lemons, grapefruit ortangerines; vegetables, such as spinach, lettuce, asparagus, cabbages,carrots, onions, tomatoes, potatoes or bell peppers; Lauraceae, such asavocado, Cinnamonium or camphor; and also tobacco, nuts, coffee,eggplants, sugarcane, tea, pepper, grapevines, hops, the plantainfamily, latex plants and ornamentals (such as bedding plants, floweringplants, shrubs, and trees). Preferably the crop plants are selected fromthe group consisting of corn, wheat, rice, soybean and also ornamentals.

The compositions according to the invention are preferably applied tomonocotylendonous crops. The term “crops” is to be understood asincluding also crops that have been rendered tolerant to herbicides likebromoxynil or classes of herbicides (such as, for example, HPPDinhibitors like isoxazoles like isoxaflutole and isoxachlortol, andtriones like mesotrione and sulcotrione, ALS inhibitors, for examplesulfonylurea like primisulfuron, prosulfuron, trifloxysulfuron,imidazolinones, triazolopyrimidines, phthalides andpyrimidyloxybenzoates, ACCase inhibitors such asaryloxyphenoxyalkanecarboxylic acids and cyclohexadiones, PROTOXinhibitors such as diphenyl ether, cyclic imides, phenyl pyrazoles,pyridines and oxadiazoles, EPSPS(5-enol-pyrovyl-shikimate-3-phosphate-synthase) inhibitors, GS(glutamine synthetase) inhibitors), as well as inhibitors ofphosphinothricin acetyltransferase, O-methyl transferase,adenylosuccinate lyase and synthase, anthranilate synthase, nitrilase,glyphosate oxidoreductase as described in Tables 1 to 3 ofUS2010/0130561.

An example of a crop that has been rendered tolerant to imidazolinones,e.g. imazamox, by conventional methods of breeding (mutagenesis) isClearfield® summer rape (Canola). Examples of crops that have beenrendered tolerant to herbicides or classes of herbicides by geneticengineering methods include glyphosate- and glufosinate-resistant maizevarieties commercially available under the trade names RoundupReady® andLibertyLink®.

The term “crops” is to be understood as including also crop plants whichhave been so transformed by the use of recombinant DNA techniques thatthey are capable of synthesising one or more selectively acting toxins,such as are known, for example, from toxin-producing bacteria,especially those of the genus Bacillus.

Toxins that can be expressed by such transgenic plants include, forexample, insecticidal proteins from Bacillus cereus or Bacilluspopilliae; or insecticidal proteins from Bacillus thuringiensis, such asδ-endotoxins, e.g. Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A,Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), e.g. Vip1,Vip2, Vip3 or Vip3A; or insecticidal proteins of bacteria colonisingnematodes, for example Photorhabdus spp. or Xenorhabdus spp., such asPhotorhabdus luminescens, Xenorhabdus nematophilus; toxins produced byanimals, such as scorpion toxins, arachnid toxins, wasp toxins and otherinsect-specific neurotoxins; toxins produced by fungi, such asStreptomycetes toxins, plant lectins, such as pea lectins, barleylectins or snowdrop lectins; agglutinins; proteinase inhibitors, such astrypsin inhibitors, serine protease inhibitors, patatin, cystatin,papain inhibitors; ribosome-inactivating proteins (RIP), such as ricin,maize-RIP, abrin, luffin, saporin or bryodin; steroid metabolismenzymes, such as 3-hydroxysteroidoxidase,ecdysteroid-UDP-glycosyl-transferase, cholesterol oxidases, ecdysoneinhibitors, HMG-COA-reductase, ion channel blockers, such as blockers ofsodium or calcium channels, juvenile hormone esterase, diuretic hormonereceptors, stilbene synthase, bibenzyl synthase, chitinases andglucanases.

In the context of the present invention there are to be understood byδ-endotoxins, for example Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A,Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for exampleVip1, Vip2, Vip3 or Vip3A, expressly also hybrid toxins, truncatedtoxins and modified toxins. Hybrid toxins are produced recombinantly bya new combination of different domains of those proteins (see, forexample, WO 02/15701). Truncated toxins, for example a truncated Cry1Ab,are known. In the case of modified toxins, one or more amino acids ofthe naturally occurring toxin are replaced. In such amino acidreplacements, preferably non-naturally present protease recognitionsequences are inserted into the toxin, such as, for example, in the caseof Cry3A055, a cathepsin-G-recognition sequence is inserted into a Cry3Atoxin (see WO 03/018810).

Examples of such toxins or transgenic plants capable of synthesisingsuch toxins are disclosed, for example, in EP-A-0 374 753, WO 93/07278,WO 95/34656, EP-A-0 427 529, EP-A-451 878 and WO 03/052073.

The processes for the preparation of such transgenic plants aregenerally known to the person skilled in the art and are described, forexample, in the publications mentioned above. Cry1-type deoxyribonucleicacids and their preparation are known, for example, from WO 95/34656,EP-A-0 367 474, EP-A-0 401 979 and WO 90/13651.

The toxin contained in the transgenic plants imparts to the plantstolerance to harmful insects. Such insects can occur in any taxonomicgroup of insects, but are especially commonly found in the beetles(Coleoptera), two-winged insects (Diptera) and moths (Lepidoptera).

Transgenic plants containing one or more genes that code for aninsecticidal resistance and express one or more toxins are known andsome of them are commercially available. Examples of such plants are:YieldGard® (maize variety that expresses a Cry1Ab toxin); YieldGardRootworm® (maize variety that expresses a Cry3Bb1 toxin); YieldGardPlus® (maize variety that expresses a Cry1Ab and a Cry3Bb1 toxin);Starlink® (maize variety that expresses a Cry9C toxin); Herculex I®(maize variety that expresses a Cry1 Fa2 toxin and the enzymephosphinothricine N-acetyltransferase (PAT) to achieve tolerance to theherbicide glufosinate ammonium); NuCOTN 33B® (cotton variety thatexpresses a Cry1Ac toxin); Bollgard I® (cotton variety that expresses aCry1Ac toxin); Bollgard HO (cotton variety that expresses a Cry1Ac and aCry2Ab toxin); VipCot® (cotton variety that expresses a Vip3A and aCry1Ab toxin); NewLeaf® (potato variety that expresses a Cry3A toxin);NatureGard®, Agrisure® GT Advantage (GA21 glyphosate-tolerant trait),Agrisure® CB Advantage (Bt11 corn borer (CB) trait) and Protecta®.

Further examples of such transgenic crops are:

1. Bt11 Maize from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31 790St. Sauveur, France, registration number C/FR/96/05/10. Geneticallymodified Zea mays which has been rendered resistant to attack by theEuropean corn borer (Ostrinia nubilalis and Sesamia nonagrioides) bytransgenic expression of a truncated Cry1Ab toxin. Bt11 maize alsotransgenically expresses the enzyme PAT to achieve tolerance to theherbicide glufosinate ammonium.

2. Bt176 Maize from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31 790St. Sauveur, France, registration number C/FR/96/05/10. Geneticallymodified Zea mays which has been rendered resistant to attack by theEuropean corn borer (Ostrinia nubilalis and Sesamia nonagrioides) bytransgenic expression of a Cry1Ab toxin. Bt176 maize also transgenicallyexpresses the enzyme PAT to achieve tolerance to the herbicideglufosinate ammonium.

3. MIR604 Maize from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31 790St. Sauveur, France, registration number C/FR/96/05/10. Maize which hasbeen rendered insect-resistant by transgenic expression of a modifiedCry3A toxin. This toxin is Cry3A055 modified by insertion of acathepsin-G-protease recognition sequence. The preparation of suchtransgenic maize plants is described in WO 03/018810.

4. MON 863 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren,B-1150 Brussels, Belgium, registration number C/DE/02/9. MON 863expresses a Cry3Bb1 toxin and has resistance to certain Coleopterainsects.

5. IPC 531 Cotton from Monsanto Europe S.A. 270-272 Avenue de Tervuren,B-1150 Brussels, Belgium, registration number C/ES/96/02.

6. 1507 Maize from Pioneer Overseas Corporation, Avenue Tedesco, 7B-1160 Brussels,

Belgium, registration number C/NL/00/10. Genetically modified maize forthe expression of the protein Cry1F for achieving resistance to certainLepidoptera insects and of the PAT protein for achieving tolerance tothe herbicide glufosinate ammonium.

7. NK603×MON 810 Maize from Monsanto Europe S.A. 270-272 Avenue deTervuren, B-1150 Brussels, Belgium, registration number C/GB/02/M3/03.Consists of conventionally bred hybrid maize varieties by crossing thegenetically modified varieties NK603 and MON 810. NK603×MON 810 Maizetransgenically expresses the protein CP4 EPSPS, obtained fromAgrobacterium sp. strain CP4, which imparts tolerance to the herbicideRoundup® (contains glyphosate), and also a Cry1Ab toxin obtained fromBacillus thuringiensis subsp. kurstaki which brings about tolerance tocertain Lepidoptera, include the European corn borer.

The term “crops” is to be understood as including also crop plants whichhave been so transformed by the use of recombinant DNA techniques thatthey are capable of synthesising antipathogenic substances having aselective action, such as, for example, the so-called“pathogenesis-related proteins” (PRPs, see e.g. EP-A-0 392 225).Examples of such antipathogenic substances and transgenic plants capableof synthesising such antipathogenic substances are known, for example,from EP-A-0 392 225, WO 95/33818, and EP-A-0 353 191. The methods ofproducing such transgenic plants are generally known to the personskilled in the art and are described, for example, in the publicationsmentioned above.

Antipathogenic substances which can be expressed by such transgenicplants include, for example, ion channel blockers, such as blockers forsodium and calcium channels, for example the viral KP1, KP4 or KP6toxins; stilbene synthases; bibenzyl synthases; chitinases; glucanases;the so-called “pathogenesis-related proteins” (PRPs; see e.g. EP-A-0 392225); antipathogenic substances produced by microorganisms, for examplepeptide antibiotics or heterocyclic antibiotics (see e.g. WO 95/33818)or protein or polypeptide factors involved in plant pathogen defence(so-called “plant disease resistance genes”, as described in WO03/000906).

The compositions according to the invention are preventively and/orcuratively valuable active ingredients in the field of pest control,even at low rates of application, which have a very favorable biocidalspectrum and are well tolerated by warm-blooded species, fish andplants. The active ingredients act against all or individualdevelopmental stages of normally sensitive, but also resistant, animalpests, such as insects or representatives of the order Acarina. Theinsecticidal or acaricidal activity of the active ingredients canmanifest itself directly, i.e. in destruction of the pests, which takesplace either immediately or only after some time has elapsed, forexample during ecdysis, or indirectly, for example in a reducedoviposition and/or hatching rate, a good activity corresponding to adestruction rate (mortality) of at least 50 to 60%.

The compositions according to the invention can be used to combat andcontrol infestations of insect pests such as Lepidoptera, Diptera,Hemiptera, Thysanoptera, Orthoptera, Dictyoptera, Coleoptera,Siphonaptera, Hymenoptera and Isoptera and also other invertebratepests, for example, acarine, nematode and mollusc pests. Insects,acarines, nematodes and molluscs are hereinafter collectively referredto as pests. The pests which may be combated and controlled by the useof the inventively used compounds include those pests associated withagriculture (which term includes the growing of crops for food and fibreproducts), horticulture and animal husbandry, companion animals,forestry and the storage of products of vegetable origin (such as fruit,grain and timber); those pests associated with the damage of man-madestructures and the transmission of diseases of man and animals; and alsonuisance pests (such as flies).

Examples of pest species which may be controlled by the compositionsaccording to the invention include: Myzus persicae (aphid), Aphisgossypii (aphid), Aphis fabae (aphid), Lygus spp. (capsids), Dysdercusspp. (capsids), Nilaparvata lugens (planthopper), Nephotettixc incticeps(leafhopper), Nezara spp. (stinkbugs), Euschistus spp. (stinkbugs),Leptocorisa spp. (stinkbugs), Frankliniella occidentalis (thrip), Thripsspp. (thrips), Leptinotarsa decemlineata (Colorado potato beetle),Anthonomus grandis (boll weevil), Aonidiella spp. (scale insects),Trialeurodes spp. (white flies), Bemisia tabaci (white fly), Ostrinianubilalis (European corn borer), Spodoptera littoralis (cottonleafworm), Heliothis virescens (tobacco budworm), Helicoverpa armigera(cotton bollworm), Helicoverpa zea (cotton bollworm), Sylepta derogata(cotton leaf roller), Pieris brassicae (white butterfly), Plutellaxylostella (diamond back moth), Agrotis spp. (cutworms), Chilosuppressalis (rice stem borer), Locusta migratoria (locust),Chortiocetes terminifera (locust), Diabrotica spp. (rootworms),Panonychus ulmi (European red mite), Panonychus citri (citrus red mite),Tetranychus urticae (two-spotted spider mite), Tetranychus cinnabarinus(carmine spider mite), Phyllocoptruta oleivora (citrus rust mite),Polyphagotarsonemus latus (broad mite), Brevipalpus spp. (flat mites),Boophilus microplus (cattle tick), Dermacentor variabilis (American dogtick), Ctenocephalides felis (cat flea), Liriomyza spp. (leafminer),Musca domestica (housefly), Aedes aegypti (mosquito), Anopheles spp.(mosquitoes), Culex spp. (mosquitoes), Lucillia spp. (blowflies),Blattella germanica (cockroach), Periplaneta americana (cockroach),Blatta orientalis (cockroach), termites of the Mastotermitidae (forexample Mastotermes spp.), the Kalotermitidae (for example Neotermesspp.), the Rhinotermitidae (for example Coptotermes formosanus,Reticulitermes flavipes, R. speratu, R. virginicus, R. hesperus, and R.santonensis) and the Termitidae (for example Globitermes sulphureus),Solenopsis geminata (fire ant), Monomorium pharaonis (pharaoh's ant),Damalinia spp. and Linognathus spp. (biting and sucking lice),Meloidogyne spp. (root knot nematodes), Globodera spp. and Heteroderaspp. (cyst nematodes), Pratylenchus spp. (lesion nematodes), Rhodopholusspp. (banana burrowing nematodes), Tylenchulus spp. (citrus nematodes),Haemonchus contortus (barber pole worm), Caenorhabditis elegans (vinegareelworm), Trichostrongylus spp. (gastro intestinal nematodes) andDeroceras reticulatum (slug).

Examples of the abovementioned pests are:

from the order Acarina, for example,Acalitus spp, Aculus spp, Acaricalus spp, Aceria spp, Acarus siro,Amblyomma spp., Argas spp., Boophilus spp., Brevipalpus spp., Bryobiaspp, Calipitrimerus spp., Chorioptes spp., Dermanyssus gallinae,Dermatophagoides spp, Eotetranychus spp, Eriophyes spp., Hemitarsonemusspp, Hyalomma spp., Ixodes spp., Olygonychus spp, Ornithodoros spp.,Polyphagotarsone latus, Panonychus spp., Phyllocoptruta oleivora,Phytonemus spp, Polyphagotarsonemus spp, Psoroptes spp., Rhipicephalusspp., Rhizoglyphus spp., Sarcoptes spp., Steneotarsonemus spp,Tarsonemus spp. and Tetranychus spp.;from the order Anoplura, for example,

Haematopinus spp., Linognathus spp., Pediculus spp., Pemphigus spp. andPhylloxera spp.;

from the order Coleoptera, for example,Agriotes spp., Amphimallon majale, Anomala orientalis, Anthonomus spp.,Aphodius spp, Astylus atromaculatus, Ataenius spp, Atomaria linearis,Chaetocnema tibialis, Cerotoma spp, Conoderus spp, Cosmopolites spp.,Cotinis nitida, Curculio spp., Cyclocephala spp, Dermestes spp.,Diabrotica spp., Diloboderus abderus, Epilachna spp., Eremnus spp.,Heteronychus arator, Hypothenemus hampei, Lagria vilosa, LeptinotarsadecemLineata, Lissorhoptrus spp., Liogenys spp, Maecolaspis spp,Maladera castanea, Megascelis spp, Melighetes aeneus, Melolontha spp.,Myochrous armatus, Orycaephilus spp., Otiorhynchus spp., Phyllophagaspp, Phlyctinus spp., Popillia spp., Psylliodes spp., Rhyssomatusaubtilis, Rhizopertha spp., Scarabeidae, Sitophilus spp., Sitotrogaspp., Somaticus spp, Sphenophorus spp, Sternechus subsignatus, Tenebriospp., Tribolium spp. and Trogoderma spp.;from the order Diptera, for example,Aedes spp., Anopheles spp, Antherigona soccata, Bactrocea oleae, Bibiohortulanus, Bradysia spp, Calliphora erythrocephala, Ceratitis spp.,Chrysomyia spp., Culex spp., Cuterebra spp., Dacus spp., Delia spp,Drosophila melanogaster, Fannia spp., Gastrophilus spp., Geomyzatripunctata, Glossina spp., Hypoderma spp., Hyppobosca spp., Liriomyzaspp., Lucilia spp., Melanagromyza spp., Musca spp., Oestrus spp.,Orseolia spp., Oscinella frit, Pegomyia hyoscyami, Phorbia spp.,Rhagoletis spp, Rivelia quadrifasciata, Scatella spp, Sciara spp.,Stomoxys spp., Tabanus spp., Tannia spp. and Tipula spp.;from the order Hemiptera, for example,Acanthocoris scabrator, Acrosternum spp, Adelphocoris lineolatus,Amblypelta nitida, Bathycoelia thalassina, Blissus spp, Cimex spp.,Clavigralla tomentosicollis, Creontiades spp, Distantiella theobroma,Dichelops furcatus, Dysdercus spp., Edessa spp, Euchistus spp., Eurydemapulchrum, Eurygaster spp., Halyomorpha halys, Horcias nobilellus,Leptocorisa spp., Lygus spp, Margarodes spp, Murgantia histrionic,Neomegalotomus spp, Nesidiocoris tenuis, Nezara spp., Nysius simulans,Oebalus insularis, Piesma spp., Piezodorus spp, Rhodnius spp.,Sahlbergella singularis, Scaptocoris castanea, Scotinophara spp.,Thyanta spp, Triatoma spp., Vatiga illudens;Acyrthosium pisum, Adalges spp, Agalliana ensigera, Agonoscenatargionii, Aleurodicus spp, Aleurocanthus spp, Aleurolobus barodensis,Aleurothrixus floccosus, Aleyrodes brassicae, Amarasca biguttula,Amritodus atkinsoni, Aonidiella spp., Aphididae, Aphis spp., Aspidiotusspp., Aulacorthum solani, Bactericera cockerelli, Bemisia spp,Brachycaudus spp, Brevicoryne brassicae, Cacopsylla spp, Cavariellaaegopodii Scop., Ceroplaster spp., Chrysomphalus aonidium, Chrysomphalusdictyospermi, Cicadella spp, Cofana spectra, Cryptomyzus spp, Cicadulinaspp, Coccus hesperidum, Dalbulus maidis, Dialeurodes spp, Diaphorinacitri, Diuraphis noxia, Dysaphis spp, Empoasca spp., Eriosoma larigerum,Erythroneura spp., Gascardia spp., Glycaspis brimblecombei, Hyadaphispseudobrassicae, Hyalopterus spp, Hyperomyzus pallidus, Idioscopusclypealis, Jacobiasca lybica, Laodelphax spp., Lecanium corni,Lepidosaphes spp., Lopaphis erysimi, Lyogenys maidis, Macrosiphum spp.,Mahanarva spp, Metcalfa pruinosa, Metopolophium dirhodum, Myndus crudus,Myzus spp., Neotoxoptera sp, Nephotettix spp., Nilaparvata spp.,Nippolachnus piri Mats, Odonaspis ruthae, Oregma lanigera Zehnter,Parabemisia myricae, Paratrioza cockerelli, Parlatoria spp., Pemphigusspp., Peregrinus maidis, Perkinsiella spp, Phorodon humuli, Phylloxeraspp, Planococcus spp., Pseudaulacaspis spp., Pseudococcus spp.,Pseudatomoscelis seriatus, Psylla spp., Pulvinaria aethiopica,Quadraspidiotus spp., Quesada gigas, Recilia dorsalis, Rhopalosiphumspp., Saissetia spp., Scaphoideus spp., Schizaphis spp., Sitobion spp.,Sogatella furcifera, Spissistilus festinus, Tarophagus Proserpina,Toxoptera spp, Trialeurodes spp, Tridiscus sporoboli, Trionymus spp,Trioza erytreae, Unaspis citri, Zygina flammigera, Zyginidiascutellaris;from the order Hymenoptera, for example,Acromyrmex, Arge spp, Atta spp., Cephus spp., Diprion spp., Diprionidae,Gilpinia polytoma, Hoplocampa spp., Lasius spp., Monomorium pharaonis,Neodiprion spp., Pogonomyrmex spp, Slenopsis invicta, Solenopsis spp.and Vespa spp.;from the order Isoptera, for example,Coptotermes spp, Corniternes cumulans, Incisitermes spp, Macrotermesspp, Mastotermes spp, Microtermes spp, Reticulitermes spp.; Solenopsisgeminate,from the order Lepidoptera, for example,Acleris spp., Adoxophyes spp., Aegeria spp., Agrotis spp., Alabamaargillaceae, Amylois spp., Anticarsia gemmatalis, Archips spp.,Argyresthia spp, Argyrotaenia spp., Autographa spp., Bucculatrixthurberiella, Busseola fusca, Cadra cautella, Carposina nipponensis,Chilo spp., Choristoneura spp., Chrysoteuchia topiaria, Clysiaambiguella, Cnaphalocrocis spp., Cnephasia spp., Cochylis spp.,Coleophora spp., Colias lesbia, Cosmophila flava, Crambus spp,Crocidolomia binotalis, Cryptophlebia leucotreta, Cydalima perspectalis,Cydia spp., Diaphania perspectalis, Diatraea spp., Diparopsis castanea,Earias spp., Eldana saccharina, Ephestia spp., Epinotia spp, Estigmeneacrea, Etiella zinckinella, Eucosma spp., Eupoecilia ambiguella,Euproctis spp., Euxoa spp., Feltia jaculiferia, Grapholita spp., Hedyanubiferana, Heliothis spp., Hellula undalis, Herpetogramma spp,Hyphantria cunea, Keiferia lycopersicella, Lasmopalpus lignosellus,Leucoptera scitella, Lithocollethis spp., Lobesia botrana, Loxostegebifidalis, Lymantria spp., Lyonetia spp., Malacosoma spp., Mamestrabrassicae, Manduca sexta, Mythimna spp, Noctua spp, Operophtera spp.,Orniodes indica, Ostrinia nubilalis, Pammene spp., Pandemis spp.,Panolis flammea, Papaipema nebris, Pectinophora gossypiela,Perileucoptera coffeella, Pseudaletia unipuncta, Phthorimaeaoperculella, Pieris rapae, Pieris spp., Plutella xylostella, Prays spp.,Pseudoplusia spp, Rachiplusia nu, Richia albicosta, Scirpophaga spp.,Sesamia spp., Sparganothis spp., Spodoptera spp., Sylepta derogate,Synanthedon spp., Thaumetopoea spp., Tortrix spp., Trichoplusia ni, Tutaabsoluta, and Yponomeuta spp.;from the order Mallophaga, for example,

Damalinea spp. and Trichodectes spp.;

from the order Orthoptera, for example,Blatta spp., Blattella spp., Gryllotalpa spp., Leucophaea maderae,Locusta spp., Neocurtilla hexadactyla, Periplaneta spp., Scapteriscusspp, and Schistocerca spp.;from the order Psocoptera, for example,

Liposcelis spp.;

from the order Siphonaptera, for example,Ceratophyllus spp., Ctenocephalides spp. and Xenopsylla cheopis;from the order Thysanoptera, for example,Calliothrips phaseoli, Frankliniella spp., Heliothrips spp,Hercinothrips spp., Parthenothrips spp, Scirtothrips aurantii,Sericothrips variabilis, Taeniothrips spp., Thrips spp;from the order Thysanura, for example,Lepisma saccharina.

The active ingredients according to the invention can be used forcontrolling, i.e. containing or destroying, pests of the abovementionedtype which occur in particular on plants, especially on useful plantsand ornamentals in agriculture, in horticulture and in forests, or onorgans, such as fruits, flowers, foliage, stalks, tubers or roots, ofsuch plants, and in some cases even plant organs which are formed at alater point in time remain protected against these pests.

Suitable target crops are, in particular, cereals, such as wheat,barley, rye, oats, rice, maize or sorghum; beet, such as sugar or fodderbeet; fruit, for example pomaceous fruit, stone fruit or soft fruit,such as apples, pears, plums, peaches, almonds, cherries or berries, forexample strawberries, raspberries or blackberries; leguminous crops,such as beans, lentils, peas or soya; oil crops, such as oilseed rape,mustard, poppies, olives, sunflowers, coconut, castor, cocoa or groundnuts; cucurbits, such as pumpkins, cucumbers or melons; fibre plants,such as cotton, flax, hemp or jute; citrus fruit, such as oranges,lemons, grapefruit or tangerines; vegetables, such as spinach, lettuce,asparagus, cabbages, carrots, onions, tomatoes, potatoes or bellpeppers; Lauraceae, such as avocado, Cinnamonium or camphor; and alsotobacco, nuts, coffee, eggplants, sugarcane, tea, pepper, grapevines,hops, the plantain family, latex plants and ornamentals.

Depending on the plant species or plant varieties, their location andgrowth conditions (soils, climate, vegetation period, diet), thetreatment according to the invention may also result in superadditiveeffects. Thus, for example, reduced application rates and/or widening ofthe activity spectrum and/or an increase in the activity of thecompositions according to the invention and compositions which lead tobetter plant growth, increased tolerance to high or lower temperatures,increased tolerance to drought or to water or soil salt content,increased flowering performance, easier harvesting acceleratedmaturation, higher harvest yields, better quality and/or highernutritional value of the harvested products, better storage abilityand/or processability of the harvested products are possible whichexceed the effects which were actually to be expected.

The compounds of formula I and plant growth regulators are generallyapplied as compositions such as emulsifiable concentrates, suspensionconcentrates, directly sprayable or dilutable solutions, spreadablepastes, dilute emulsions, soluble powders, dispersible powders, wettablepowders, dusts, granules or encapsulations in polymeric substances,which comprise—at least—one of the active ingredients according to theinvention and which are to be selected to suit the intended aims and theprevailing circumstances.

In these compositions, the active ingredient is employed in pure form, asolid active ingredient for example in a specific particle size, or,preferably, together with—at least—one of the auxiliaries conventionallyused in the art of formulation, such as extenders, for example solventsor solid carriers, or such as surface-active compounds (surfactants).

Examples of suitable solvents are: unhydrogenated or partiallyhydrogenated aromatic hydrocarbons, preferably the fractions C8 to C12of alkylbenzenes, such as xylene mixtures, alkylated naphthalenes ortetrahydronaphthalene, aliphatic or cycloaliphatic hydrocarbons, such asparaffins or cyclohexane, alcohols such as ethanol, propanol or butanol,glycols and their ethers and esters such as propylene glycol,dipropylene glycol ether, ethylene glycol or ethylene glycol monomethylether or ethylene glycol monoethyl ether, ketones, such ascyclohexanone, isophorone or diacetone alcohol, strongly polar solvents,such as N-methylpyrrolid-2-one, dimethyl sulfoxide orN,N-dimethylformamide, water, unepoxidized or epoxidized vegetable oils,such as unexpodized or epoxidized rapeseed, castor, coconut or soya oil,and silicone oils.

Solid carriers which are used for example for dusts and dispersiblepowders are, as a rule, ground natural minerals such as calcite, talc,kaolin, montmorillonite or attapulgite. To improve the physicalproperties, it is also possible to add highly disperse silicas or highlydisperse absorbtive polymers. Suitable particulate adsorptive carriersfor granules are porous types, such as pumice, brick grit, sepiolite orbentonite, and suitable non-sorptive carrier materials are calcite orsand. In addition, a large number of granulated materials of inorganicor organic nature can be used, in particular dolomite or comminutedplant residues.

Suitable surface-active compounds are, depending on the type of theactive ingredient to be formulated, non-ionic, cationic and/or anionicsurfactants or surfactant mixtures which have good emulsifying,dispersing and wetting properties. The surfactants mentioned below areonly to be considered as examples; a large number of further surfactantswhich are conventionally used in the art of formulation and suitableaccording to the invention are described in the relevant literature.

Suitable non-ionic surfactants are, especially, polyglycol etherderivatives of aliphatic or cycloaliphatic alcohols, of saturated orunsaturated fatty acids or of alkyl phenols which may containapproximately 3 to approximately 30 glycol ether groups andapproximately 8 to approximately 20 carbon atoms in the (cyclo)aliphatichydrocarbon radical or approximately 6 to approximately 18 carbon atomsin the alkyl moiety of the alkyl phenols. Also suitable arewater-soluble polyethylene oxide adducts with polypropylene glycol,ethylenediaminopo

dypropylene glycol or alkyl polypropylene glycol having 1 toapproximately 10 carbon atoms in the alkyl chain and approximately 20 toapproximately 250 ethylene glycol ether groups and approximately 10 toapproximately 100 propylene glycol ether groups. Normally, theabovementioned compounds contain 1 to approximately 5 ethylene glycolunits per propylene glycol unit. Examples which may be mentioned arenonylphenoxypolyethoxyethanol, castor oil polyglycol ether,polypropylene glycol/polyethylene oxide adducts, tributylpheno

xypolyethoxyethanol, polyethylene glycol oroctylphenoxypolyethoxyethanol. Also suitable are fatty acid esters ofpolyoxyethylene sorbitan, such as polyoxyethylene sorbitan trioleate.

The cationic surfactants are, especially, quarternary ammonium saltswhich generally have at least one alkyl radical of approximately 8 toapproximately 22 C atoms as substituents and as further substituents(unhalogenated or halogenated) lower alkyl or hydroxyalkyl or benzylradicals. The salts are preferably in the form of halides,methylsulfates or ethylsulfates. Examples are stearyltrimethylammoniumchloride and benzylbis(2-chloroethyl)ethyhammonium bromide.

Examples of suitable anionic surfactants are water-soluble soaps orwater-soluble synthetic surface-active compounds. Examples of suitablesoaps are the alkali, alkaline earth or (unsubstituted or substituted)ammonium salts of fatty acids having approximately 10 to approximately22 C atoms, such as the sodium or potassium salts of oleic or stearicacid, or of natural fatty acid mixtures which are obtainable for examplefrom coconut or tall oil; mention must also be made of the fatty acidmethyl taurates. However, synthetic surfactants are used morefrequently, in particular fatty sulfonates, fatty sulfates, sulfonatedbenzimidazole derivatives or alkylaryl sulfonates. As a rule, the fattysulfonates and fatty sulfates are present as alkali, alkaline earth or(substituted or unsubstituted) ammonium salts and they generally have analkyl radical of approximately 8 to approximately 22 C atoms, alkyl alsoto be understood as including the alkyl moiety of acyl radicals;examples which may be mentioned are the sodium or calcium salts oflignosulfonic acid, of the dodecylsulfuric ester or of a fatty alcoholsulfate mixture prepared from natural fatty acids. This group alsoincludes the salts of the sulfuric esters and sulfonic acids of fattyalcohol/ethylene oxide adducts. The sulfonated benzimidazole derivativespreferably contain 2 sulfonyl groups and a fatty acid radical ofapproximately 8 to approximately 22 C atoms. Examples ofalkylarylsulfonates are the sodium, calcium or triethanolammonium saltsof decylbenzenesulfonic acid, of dibutylnaphthalenesulfonic acid or of anaphthalenesulfonic acid/formaldehyde condensate. Also possible are,furthermore, suitable phosphates, such as salts of the phosphoric esterof a p-nonylphenol/(4-14)ethylene oxide adduct, or phospholipids.Further suitable phosphates are tris-esters of phosphoric acid withaliphatic or aromatic alcohols and/or bis-esters of alkyl phosphonicacids with aliphatic or aromatic alcohols, which are a high performanceoil-type adjuvant. These tris-esters have been described, for example,in WO0147356, WO0056146, EP-A-0579052 or EP-A-1018299 or arecommercially available under their chemical name. Preferred tris-estersof phosphoric acid for use in the new compositions aretris-(2-ethylhexyl) phosphate, tris-n-octyl phosphate andtris-butoxyethyl phosphate, where tris-(2-ethylhexyl) phosphate is mostpreferred. Suitable bis-ester of alkyl phosphonic acids arebis-(2-ethylhexyl)-(2-ethylhexyl)-phosphonate,bis-(2-ethylhexyl)-(n-octyl)-phosphonate, dibutyl-butyl phosphonate andbis(2-ethylhexyl)-tripropylene-phosphonate, wherebis-(2-ethylhexyl)-(n-octyl)-phosphonate is particularly preferred.

The compositions according to the invention can preferably additionallyinclude an additive comprising an oil of vegetable or animal origin, amineral oil, alkyl esters of such oils or mixtures of such oils and oilderivatives. The amount of oil additive used in the compositionaccording to the invention is generally from 0.01 to 10%, based on thespray mixture. For example, the oil additive can be added to the spraytank in the desired concentration after the spray mixture has beenprepared. Preferred oil additives comprise mineral oils or an oil ofvegetable origin, for example rapeseed oil such as ADIGOR® and MERO®,olive oil or sunflower oil, emulsified vegetable oil, such as AMIGO®(Rhone-Poulenc Canada Inc.), alkyl esters of oils of vegetable origin,for example the methyl derivatives, or an oil of animal origin, such asfish oil or beef tallow. A preferred additive contains, for example, asactive components essentially 80% by weight alkyl esters of fish oilsand 15% by weight methylated rapeseed oil, and also 5% by weight ofcustomary emulsifiers and pH modifiers. Especially preferred oiladditives comprise alkyl esters of C₈-C₂₂ fatty acids, especially themethyl derivatives of C₁₂-C₁₈ fatty acids, for example the methyl estersof lauric acid, palmitic acid and oleic acid, being important. Thoseesters are known as methyl laurate (CAS-111-82-0), methyl palmitate(CAS-112-39-0) and methyl oleate (CAS-112-62-9). A preferred fatty acidmethyl ester derivative is Emery® 2230 and 2231 (Cognis GmbH). Those andother oil derivatives are also known from the Compendium of HerbicideAdjuvants, 5th Edition, Southern Illinois University, 2000. Also,alkoxylated fatty acids can be used as additives in the inventivecompositions as well as polymethylsiloxane based additives, which havebeen described in WO08/037,373.

The application and action of the oil additives can be further improvedby combining them with surface-active substances, such as non-ionic,anionic or cationic surfactants. Examples of suitable anionic, non-ionicand cationic surfactants are listed on pages 7 and 8 of WO 97/34485.Preferred surface-active substances are anionic surfactants of thedodecyl-benzylsulfonate type, especially the calcium salts thereof, andalso non-ionic surfactants of the fatty alcohol ethoxylate type. Specialpreference is given to ethoxylated C₁₂-C₂₂ fatty alcohols having adegree of ethoxylation of from 5 to 40. Examples of commerciallyavailable surfactants are the Genapol types (Clariant AG). Alsopreferred are silicone surfactants, especially polyalkyl-oxide-modifiedheptamethyltrisiloxanes, which are commercially available e.g. as SilwetL-77®, and also perfluorinated surfactants. The concentration ofsurface-active substances in relation to the total additive is generallyfrom 1 to 30% by weight. Examples of oil additives that consist ofmixtures of oils or mineral oils or derivatives thereof with surfactantsare Edenor ME SU®, Turbocharge® (Syngenta AG, CH) and Actipron® (BP OilUK Limited, GB).

The said surface-active substances may also be used in the formulationsalone, that is to say without oil additives.

Furthermore, the addition of an organic solvent to the oiladditive/surfactant mixture can contribute to a further enhancement ofaction. Suitable solvents are, for example, Solvesso® (ESSO) andAromatic Solvent® (Exxon Corporation). The concentration of suchsolvents can be from 10 to 80% by weight of the total weight. Such oiladditives, which may be in admixture with solvents, are described, forexample, in U.S. Pat. No. 4,834,908. A commercially available oiladditive disclosed therein is known by the name MERGE® (BASFCorporation). A further oil additive that is preferred according to theinvention is SCORE® (Syngenta Crop Protection Canada.)

In addition to the oil additives listed above, in order to enhance theactivity of the compositions according to the invention it is alsopossible for formulations of alkylpyrrolidones, (e.g. Agrimax®) to beadded to the spray mixture. Formulations of synthetic latices, such as,for example, polyacrylamide, polyvinyl compounds or poly-1-p-menthene(e.g. Bond®, Courier® or Emerald®) can also be used. Solutions thatcontain propionic acid, for example Eurogkem Pen-e-trate®, can also bemixed into the spray mixture as activity-enhancing agents.

As a rule, the compositions comprise 0.1 to 99%, especially 0.1 to 95%,of active ingredient of thre formula land 1 to 99.9%, especially 5 to99.9%, of at least one solid or liquid adjuvant, it being possible as arule for 0 to 25%, especially 0.1 to 20%, of the composition to besurfactants (% in each case meaning percent by weight). Whereasconcentrated compositions tend to be preferred for commercial goods, theend consumer as a rule uses dilute compositions which have substantiallylower concentrations of active ingredient.

The compositions can also comprise further solid or liquid auxiliaries,such as stabilizers, for example unepoxidized or epoxidized vegetableoils (for example epoxidized coconut oil, rapeseed oil or soya oil),antifoams, for example silicone oil, preservatives, viscosityregulators, binders and/or tackifiers; fertilizers, in particularnitrogen containing fertilizers such as ammonium nitrates and urea asdescribed in WO08/017,388, which can enhance the efficacy of theinventive compounds; or other active ingredients for achieving specificeffects, for example ammonium or phosphonium salts, in particularhalides, (hydrogen)sulphates, nitrates, (hydrogen)carbonates, citrates,tartrates, formiates and acetates, as described in WO07/068,427 andWO07/068,428, which also can enhance the efficacy of the inventivecompounds and which can be used in combination with penetrationenhancers such as alkoxalated fatty acids; bactericides, fungicides,nematocides, plant activators, molluscicides or herbicides.

The compositions according to the invention are prepared in a mannerknown per se, in the absence of auxiliaries for example by grinding,screening and/or compressing a solid active ingredient and in thepresence of at least one auxiliary for example by intimately mixingand/or grinding the active ingredient with the auxiliary (auxiliaries).These processes for the preparation of the compositions and the use ofthe compounds I for the preparation of these compositions are also asubject of the invention.

In another aspect the present invention provides a method of combatingand controlling pests which comprises treating the pests or the locus ofthe pests or the plant susceptible to attack by a pest with aninsecticidally, nematicidally or mollusicidally effective amount of acomposition according to this invention.

The application methods for the compositions, that is the methods ofcontrolling pests of the abovementioned type, such as spraying,atomizing, dusting, brushing on, dressing, scattering or pouring—whichare to be selected to suit the intended aims of the prevailingcircumstances—and the use of the compositions for controlling pests areother subjects of the invention. Typical rates of concentration arebetween 0.1 and 1000 ppm, preferably between 0.1 and 500 ppm, of activeingredient. The rate of application per hectare is generally 1 to 2000 gof active ingredient per hectare, in particular 10 to 1000 g/ha,preferably 10 to 600 g/ha.

A preferred method of application in the field of crop protection isapplication to the foliage of the plants (foliar application), it beingpossible to select frequency and rate of application to match the dangerof infestation with the pest in question. Alternatively, the activeingredient can reach the plants via the root system (systemic action),by drenching the locus of the plants with a liquid composition or byincorporating the active ingredient in solid form into the locus of theplants, for example into the soil, for example in the form of granules(soil application). In the case of paddy rice crops, such granules canbe metered into the flooded paddy-field.

The compositions according to the invention are also suitable for theprotection of plant propagation material, for example seeds, such asfruit, tubers or kernels, or nursery plants, against pests of theabovementioned type. The propagation material can be treated with thecompositions prior to planting, for example seed can be treated prior tosowing. Alternatively, the compositions can be applied to seed kernels(coating), either by soaking the kernels in a liquid composition or byapplying a layer of a solid composition. It is also possible to applythe compositions when the propagation material is planted to the site ofapplication, for example into the seed furrow during drilling. Thesetreatment methods for plant propagation material and the plantpropagation material thus treated are further subjects of the invention.

Further methods of application of the compositions according to theinvention comprise drip application onto the soil, dipping of parts ofplants such as roots bulbs or tubers, drenching the soil, as well assoil injection. These methods are known in the art.

In order to apply a composition according to the invention as aninsecticide, acaricide, nematicide, or molluscicide to a pest, a locusof pest, or to a plant susceptible to attack by a pest, a compound offormula I and, optionally, the plant growth regulator, are usuallyformulated into a composition which includes, in addition to thecompound of formula I and, optionally, the plant growth regulator, asuitable inert diluent or carrier and, optionally, a formulationadjuvant in form of a surface active agent (SFA) as described herein or,for example, in EP-B-1062217. SFAs are chemicals which are able tomodify the properties of an interface (for example, liquid/solid,liquid/air or liquid/liquid interfaces) by lowering the interfacialtension and thereby leading to changes in other properties (for exampledispersion, emulsification and wetting). It is preferred that allcompositions (both solid and liquid formulations) comprise, by weight,0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of acompound of formula I and, optionally, the plant growth regulator. Thecomposition is generally used for the control of pests such that acompound of formula I and, optionally, the plant growth regulator, isapplied at a rate of from 0.1 g to 10 kg per hectare, preferably from 1g to 6 kg per hectare, more preferably from 1 g to 1 kg per hectare.

When used in a seed dressing, a compound of formula I is used at a rateof 0.0001 g to 10 g (for example 0.001 g or 0.05 g), preferably 0.005 gto 10 g, more preferably 0.005 g to 4 g, per kilogram of seed.

The compositions can be chosen from a number of formulation types,including dustable powders (DP), soluble powders (SP), water solublegranules (SG), water dispersible granules (WG), wettable powders (WP),granules (GR) (slow or fast release), soluble concentrates (SL), oilmiscible liquids (OL), ultra low volume liquids (UL), emulsifiableconcentrates (EC), dispersible concentrates (DC), emulsions (both oil inwater (EW) and water in oil (EO)), micro-emulsions (ME), suspensionconcentrates (SC), oil-based suspension concentrate (OD), aerosols,fogging/smoke formulations, capsule suspensions (CS) and seed treatmentformulations. The formulation type chosen in any instance will dependupon the particular purpose en-visaged and the physical, chemical andbiological properties of the a compound of formula I and, optionally,the plant growth regulator.

Dustable powders (DP) may be prepared by mixing a compound of formula Iand, optionally, the plant growth regulator, with one or more soliddiluents (for example natural clays, kaolin, pyrophyllite, bentonite,alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths,calcium phosphates, calcium and magnesium carbonates, sulphur, lime,flours, talc and other organic and inorganic solid carriers) andmechanically grinding the mixture to a fine powder.

Soluble powders (SP) may be prepared by mixing a compound of formula Iand, optionally, the plant growth regulator with one or morewater-soluble inorganic salts (such as sodium bicarbonate, sodiumcarbonate or magnesium sulphate) or one or more water-soluble organicsolids (such as a polysaccharide) and, optionally, one or more wettingagents, one or more dispersing agents or a mixture of said agents toimprove water dispersibility/solubility. The mixture is then ground to afine powder. Similar compositions may also be granulated to form watersoluble granules (SG).

Wettable powders (WP) may be prepared by mixing a compound of formula Iand, optionally, the plant growth regulator with one or more soliddiluents or carriers, one or more wetting agents and, preferably, one ormore dispersing agents and, optionally, one or more suspending agents tofacilitate the dispersion in liquids. The mixture is then ground to afine powder. Similar compositions may also be granulated to form waterdispersible granules (WG).

Granules (GR) may be formed either by granulating a mixture of acompound of formula I and, optionally, the plant growth regulator andone or more powdered solid diluents or carriers, or from pre-formedblank granules by absorbing a compound of formula I (or a solutionthereof, in a suitable agent) in a porous granular material (such aspumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceousearths or ground corn cobs) or by adsorbing a compound of formula I (ora solution thereof, in a suitable agent) on to a hard core material(such as sands, silicates, mineral carbonates, sulphates or phosphates)and drying if necessary. Agents which are commonly used to aidabsorption or adsorption include solvents (such as aliphatic andaromatic petroleum solvents, alcohols, ethers, ketones and esters) andsticking agents (such as polyvinyl acetates, polyvinyl alcohols,dextrins, sugars and vegetable oils). One or more other additives mayalso be included in granules (for example an emulsifying agent, wettingagent or dispersing agent).

Dispersible Concentrates (DC) may be prepared by dissolving a compoundof formula I and, optionally, the plant growth regulator in water or anorganic solvent, such as a ketone, alcohol or glycol ether. Thesesolutions may contain a surface active agent (for example to improvewater dilution or prevent crystallisation in a spray tank).

Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may beprepared by dissolving a compound of formula I and, optionally, theplant growth regulator, in an organic solvent (optionally containing oneor more wetting agents, one or more emulsifying agents or a mixture ofsaid agents). Suitable organic solvents for use in ECs include aromatichydrocarbons (such as alkylbenzenes or alkylnaphthalenes, exemplified bySOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a RegisteredTrade Mark), ketones (such as cyclohexanone or methylcyclohexanone) andalcohols (such as benzyl alcohol, furfuryl alcohol or butanol),N-alkylpyrrolidones (such as N-methylpyrrolidone or N-octylpyrrolidone),dimethyl amides of fatty acids (such as C₈-C₁₀ fatty acid dimethylamide)and chlorinated hydrocarbons. An EC product may spontaneously emulsifyon addition to water, to produce an emulsion with sufficient stabilityto allow spray application through appropriate equipment. Preparation ofan EW involves obtaining a compound of formula I and, optionally, theplant growth regulator, either as a liquid (if it is not a liquid atroom temperature, it may be melted at a reasonable temperature,typically below 70° C.) or in solution (by dissolving it in anappropriate solvent) and then emulsifiying the resultant liquid orsolution into water containing one or more SFAs, under high shear, toproduce an emulsion. Suitable solvents for use in EWs include vegetableoils, chlorinated hydrocarbons (such as chlorobenzenes), aromaticsolvents (such as alkylbenzenes or alkylnaphthalenes) and otherappropriate organic solvents which have a low solubility in water.

Microemulsions (ME) may be prepared by mixing water with a blend of oneor more solvents with one or more SFAs, to produce spontaneously athermodynamically stable isotropic liquid formulation. A compound offormula I and, optionally, the plant growth regulator, is presentinitially in either the water or the solvent/SFA blend. Suitablesolvents for use in MEs include those hereinbefore described for use inin ECs or in EWs. An ME may be either an oil-in-water or a water-in-oilsystem (which system is present may be determined by conductivitymeasurements) and may be suitable for mixing water-soluble andoil-soluble pesticides in the same formulation. An ME is suitable fordilution into water, either remaining as a microemulsion or forming aconventional oil-in-water emulsion.

Suspension concentrates (SC) may comprise aqueous or non-aqueoussuspensions of finely divided insoluble solid particles of a compound offormula I and, optionally, the plant growth regulator. SCs may beprepared by ball or bead milling the solid compound of formula I in asuitable medium, optionally with one or more dispersing agents, toproduce a fine particle suspension of the compound. One or more wettingagents may be included in the composition and a suspending agent may beincluded to reduce the rate at which the particles settle.Alternatively, a compound of formula I and, optionally, the plant growthregulator, may be dry milled and added to water, containing agentshereinbefore described, to produce the desired end product.

Oil-based suspension concentrate (OD) may be prepared similarly bysuspending finely divided insoluble solid particles of a compound offormula I and, optionally, the plant growth regulator, in an organicfluid (for example at least one mineral oil or vegetable oil). ODs mayfurther comprise at least one penetration promoter (for example analcohol ethoxylate or a related compound), at least one non-ionicsurfactants and/or at least one anionic surfactant, and optionally atleast one additive from the group of emulsifiers, foam-inhibitingagents, preservatives, anti-oxidants, dyestuffs, and/or inert fillermaterials. An OD is intended and suitable for dilution with water beforeuse to produce a spray solution with sufficient stability to allow sprayapplication through appropriate equipment.

Aerosol formulations comprise a compound of formula I and plant growthregulator and a suitable propellant (for example n-butane). A compoundof formula I and plant growth regulator may also be dissolved ordispersed in a suitable medium (for example water or a water miscibleliquid, such as n-propanol) to provide compositions for use innon-pressurised, hand-actuated spray pumps.

A compound of formula I and plant growth regulator may be mixed in thedry state with a pyrotechnic mixture to form a composition suitable forgenerating, in an enclosed space, a smoke containing the compound.

Capsule suspensions (CS) may be prepared in a manner similar to thepreparation of EW formulations but with an additional polymerisationstage such that an aqueous dispersion of oil droplets is obtained, inwhich each oil droplet is encapsulated by a polymeric shell and containsa compound of formula I and, optionally, the plant growth regulator,and, optionally, a carrier or diluent therefor. The polymeric shell maybe produced by either an interfacial polycondensation reaction or by acoacervation procedure. The compositions may provide for controlledrelease of a compound of formula I and, optionally, the plant growthregulator, and they may be used for seed treatment. A compound offormula I and plant growth regulator may also be formulated in abiodegradable polymeric matrix to provide a slow, controlled release ofthe compound.

A compound of formula I and the plant growth regulator may also beformulated for use as a seed treatment, for example as a powdercomposition, including a powder for dry seed treatment (DS), a watersoluble powder (SS) or a water dispersible powder for slurry treatment(WS), or as a liquid composition, including a flowable concentrate (FS),a solution (LS) or a capsule suspension (CS). The preparations of DS,SS, WS, FS and LS compositions are very similar to those of,respectively, DP, SP, WP, SC, OD and DC compositions described above.Compositions for treating seed may include an agent for assisting theadhesion of the composition to the seed (for example a mineral oil or afilm-forming barrier).

A composition used according to the present invention may include one ormore additives to improve the biological performance of the composition(for example by improving wetting, retention or distribution onsurfaces; resistance to rain on treated surfaces; or uptake or mobilityof a compound of formula I and, optionally, the plant growth regulator).Such additives include surface active agents (SFAs), spray additivesbased on oils, for example certain mineral oils, vegetable oils ornatural plant oils (such as soy bean and rape seed oil), and blends ofthese with other bio-enhancing adjuvants (ingredients which may aid ormodify the action of a compound of formula I and, optionally, the plantgrowth regulator). Increasing the effect of a compound of formula I mayfor example be achieved by adding ammonium and/or phosphonium salts,and/or optionally at least one penetration promotor such as fattyalcohol alkoxylates (for example rape oil methyl ester) or vegetable oilesters.

Wetting agents, dispersing agents and emulsifying agents may be surfaceactive agents (SFAs) of the cationic, anionic, amphoteric or non-ionictype.

Suitable SFAs of the cationic type include quaternary ammonium compounds(for example cetyltrimethyl ammonium bromide), imidazolines and aminesalts.

Suitable anionic SFAs include alkali metals salts of fatty acids, saltsof aliphatic monoesters of sulphuric acid (for example sodium laurylsulphate), salts of sulphonated aromatic compounds (for example sodiumdodecylbenzenesulphonate, calcium dodecylbenzenesulphonate,butylnaphthalene sulphonate and mixtures of sodium di-isopropyl- andtri-isopropyl-naphthalene sulphonates), ether sulphates, alcohol ethersulphates (for example sodium laureth-3-sulphate), ether carboxylates(for example sodium laureth-3-carboxylate), phosphate esters (productsfrom the reaction between one or more fatty alcohols and phosphoric acid(predominately mono-esters) or phosphorus pentoxide (predominatelydi-esters), for example the reaction between lauryl alcohol andtetraphosphoric acid; additionally these products may be ethoxylated),sulphosuccinamates, paraffin or olefine sulphonates, taurates andlignosulphonates.

Suitable SFAs of the amphoteric type include betaines, propionates andglycinates.

Suitable SFAs of the non-ionic type include condensation products ofalkylene oxides, such as ethylene oxide, propylene oxide, butylene oxideor mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetylalcohol) or with alkylphenols (such as octylphenol, nonylphenol oroctylcresol); partial esters derived from long chain fatty acids orhexitol anhydrides; condensation products of said partial esters withethylene oxide; block polymers (comprising ethylene oxide and propyleneoxide); alkanolamides; simple esters (for example fatty acidpolyethylene glycol esters); amine oxides (for example lauryl dimethylamine oxide); and lecithins.

Suitable suspending agents include hydrophilic colloids (such aspolysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose)and swelling clays (such as bentonite or attapulgite).

The compound of formula I and the plant growth regulator may be appliedby any of the known means of applying pesticidal compounds. For example,it may be applied to the pests or to a locus of the pests (such as ahabitat of the pests, or a growing plant liable to infestation by thepests) or to any part of the plant, including the foliage, stems,branches or roots, to the seed before it is planted or to other media inwhich plants are growing or are to be planted (such as soil surroundingthe roots, the soil generally, paddy water or hydroponic culturesystems), directly or it may be sprayed on, dusted on, applied bydipping, applied as a cream or paste formulation, applied as a vapour orapplied through distribution or incorporation of a composition (such asa granular composition or a composition packed in a water-soluble bag)in soil or an aqueous environment.

The compound of formula I and the plant growth regulator may also beinjected into plants or sprayed onto vegetation using electrodynamicspraying techniques or other low volume methods, or applied by land oraerial irrigation systems.

Compositions for use as aqueous preparations (aqueous solutions ordispersions) are generally supplied in the form of a concentratecontaining a high proportion of the active ingredient, the concentratebeing added to water before use. These concentrates, which may includeDCs, SCs, ODs, ECs, EWs, MEs SGs, SPs, WPs, WGs and CSs, are oftenrequired to withstand storage for prolonged periods and, after suchstorage, to be capable of addition to water to form aqueous preparationswhich remain homogeneous for a sufficient time to enable them to beapplied by conventional spray equipment. Such aqueous preparations maycontain varying amounts of a compound of formula I (for example 0.0001to 10%, by weight) depending upon the purpose for which they are to beused.

A compound of formula I and the plant growth regulator may be used inmixtures with fertilisers (for example nitrogen-, potassium- orphosphorus-containing fertilisers, and more particularly ammoniumnitrate and/or urea fertilizers). Suitable formulation types includegranules of fertiliser. The mixtures suitably contain up to 25% byweight of the compound of formula I.

The invention therefore also provides a fertiliser compositioncomprising a fertiliser and a compound of formula I and, optionally, theplant growth regulator.

The compositions of this invention may contain other compounds havingbiological activity, for example micronutrients, saccharides, aminoacids, flavonoids, quinines; or other plant activators and/orstimulators and/or growth regulators like for example natural orsynthetic hormones, phytohormones such as auxins, brassinosteroids,gibberellins, polyamines, abscisic acid, cytokinins, jasmonates,cis-jasmonates, strigolactones, salicylic acid, ethylene,1-methylcyclopropene, or derivatives thereof; or compounds which possessfungicidal, herbicidal, safening, insecticidal, nematicidal oracaricidal activity.

Although it is believed that the present method can be applied to a seedin any physiological state, it is preferred that the seed be in asufficiently durable state that it incurs no damage during the treatmentprocess. Typically, the seed would be a seed that had been harvestedfrom the field; removed from the plant; and separated from any cob,stalk, outer husk, and surrounding pulp or other non-seed plantmaterial. The seed would preferably also be biologically stable to theextent that the treatment would cause no biological damage to the seed.It is believed that the treatment can be applied to the seed at any timebetween harvest of the seed and sowing of the seed or during the sowingprocess (seed directed applications). The seed may also be primed eitherbefore or after the treatment.

Even distribution of the compound and adherence thereof to the seeds isdesired during propagation material treatment. Treatment could vary froma thin film (dressing) of a formulation containing the compound, forexample, a mixture of active ingredient(s), on a plant propagationmaterial, such as a seed, where the original size and/or shape arerecognizable to an intermediary state (such as a coating) and then to athicker film (such as pelleting with many layers of different materials(such as carriers, for example, clays; different formulations, such asof other active ingredients; polymers; and colourants) where theoriginal shape and/or size of the seed is no longer recognisable intothe controlled release material or applied between layers of materials,or both.

The seed treatment occurs to an unsown seed, and the term “unsown seed”is meant to include seed at any period between the harvest of the seedand the sowing of the seed in the ground for the purpose of germinationand growth of the plant.

Treatment to an unsown seed is not meant to include those practices inwhich the active ingredient is applied to the soil but would include anyapplication practice that would target the seed during the plantingprocess.

Preferably, the treatment occurs before sowing of the seed so that thesown seed has been pre-treated with the compound. In particular, seedcoating or seed pelleting are preferred in the treatment of thecompound. As a result of the treatment, the compound is adhered on tothe seed and therefore available for pest control. The treated seeds canbe stored, handled, sowed and tilled in the same manner as any otheractive ingredient treated seed.

According to the present invention, the plant growth regulator can beapplied alone or together with the compound of the formula I before orafter emergence of the plants. The treatment of the plants or the seedmaterial with the plant growth regulator can therefore take place inprinciple independently of the time of application of the compound ofthe formula I. The treatment of the plant by simultaneous application ofthe compound of the formula I and plant growth regulator (e.g. in theform of a tank mixture) is generally preferred.

The invention is illustrated by the following preparation examples. TheH-NMR data of certain compounds of this invention show line broadeningat room temperature, suggesting the existence of plural conformationalisomers due to, for example keto-enol tautomerism, hindered rotation,ring inversion in the piperidine moitey or nitrogen inversion at thepiperidine N—OR center. Broad signals have been labeled with ‘br’accordingly.

EXAMPLE 1 Preparation of Carbonic acid ethyl ester8-methoxy-1-methyl-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1.2) Step 1: Preparation of4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2.2) [Two-Steps (Amide N-Alkylation and Cyclisation), One-PotProcedure]

To a solution of1-methoxy-4-[2-(2,4,6-trimethyl-phenyl)-acetylamino]-piperidine-4-carboxylicacid methyl ester [prepared according to WO09/049,851] (850 mg, 2.44mmol) in dimethylformamide (20 ml) at 0° C. was added sodium hydride(122 mg, 55% w/w dispersion in mineral oil, 2.81 mmol) in two portions.The reaction mixture was stirred at 0° C. for one hour, treated withmethyl iodide (0.175 ml, 398 mg, 2.81 mmol) dropwise, and furtherstirred at 0° C. for one hour and at room temperature for 3 hours. Tothe mixture recooled at 0° C. was added sodium methoxide (198 mg, 3.66mmol) in one portion, and stirring continued at room temperature for 2hours, at 40° C. for 30 minutes and after further addition of sodiummethoxide (˜20 mg) at 50° C. for 45 minutes. The reaction mixture waspoured on iced aqueous ammonium chloride, acidified to pH 5-6 with anaqueous HCl solution and thoroughly extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated. The crude oily product was purified bychromatography on silica gel (ethyl acetate), and further trituratedwith cold diethyl ether, filtered and dried. Yield: 338 mg of4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2.2) as a solid, mp 241-243° C.

¹H-NMR (CD₃OD): 1.44 (br m, 1H), 1.72 (br m, 1H), 2.10 (s, 6H), 2.25 (s,3H), 2.33 (br m, 1H), 2.48 (br m, 1H), 2.89 (br signal, 3H), 3.20 (br m,1H), 3.27-3.43 (br signals, total 3H), 3.54 (s, 3H), 6.89 (s, 2H).

LC/MS (ES+): 331 (M+H)+, LC/MS (ES−): 329 (M−H)⁻

Step 2: Preparation of carbonic acid ethyl ester8-methoxy-1-methyl-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (title compound P1.2)

To a solution of4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(238 mg, 0.72 mmol), triethylamine (0.15 ml, 109 mg, 1.08 mmol) and4-dimethylaminopyridine (2 mg) in tetrahydrofuran (10 ml) at 0° C. wasadded ethyl chloroformate (0.075 ml, 85 mg, 0.79 mmol) dropwise. Thesuspension was stirred at 0° C. for one hour. The reaction mixture wasdiluted with ethyl acetate and water, the layers separated, the aqueousphase extracted with ethyl acetate, the combined organic phases washedwith brine, dried over sodium sulfate and concentrated. The residue waspurified by chromatography on silica gel (ethyl acetate/heptane 5:1).Yield: 145 mg of carbonic acid ethyl ester8-methoxy-1-methyl-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (title compound P1.2) as a white solid, mp 134-136° C.

¹H-NMR (CDCl₃): 1.05 (t, 3H), 1.59 (br m, 1H), 1.83 (br m, 1H), 2.15 (s,6H), 2.25 (s, 3H), 2.36 (br m, 2H), 2.88 (br m, 1H), 2.95 (br s, 3H),3.22 (br m, 1H), 3.38 (m, 2H), 3.55 (s, 3H), 3.98 (q, 2H), 6.84 (s, 2H).

LC/MS (ES+): 403 (M+H)⁺

EXAMPLE 2 Preparation of4-Hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2.2) Step 1: Preparation of4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P3.4)

To a suspension of4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one[prepared according to WO09/049,851] (67.0 g, 211.7 mmol) in acetone(900 ml) was added potassium carbonate (35.1 g, 254.1 mmol), followed bybenzyl bromide (35.3 ml, 50.7 g, 296.4 mmol) dropewise. The suspensionwas stirred at reflux for one hour, then poured on ice water and ethylacetate. The resulting precipitate was filtered off, dissolved inmethylene chloride, dried over sodium sulfate, concentrated and driedover phosphorus pentoxide under vacuum at 50° C. overnight to afford afirst crop of product as a white solid (55.8 g). The layers of themother liquor were separated, the aqueous phase extracted with ethylacetate, the combined organic phases washed with brine, dried oversodium sulfate and concentrated. The residue was suspended in diethylether, filtered and dried to further deliver 22.6 g of product. Yield:78.4 g of4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P3.4) as a solid, mp 184-186° C.

¹H-NMR (CDCl₃): 1.66 (m, 2H), 2.11 (s, 6H), 2.28 (s, 3H), 2.33 (m, 2H),2.47 (m, 2H), 3.45 (m, 2H), 3.55 (s, 3H), 4.68 (s, 2H), 6.13 (br s, 1H),6.87 (s, 2H), 7.04 (m, 2H), 7.28 (m, 3H).

LC/MS (ES+): 407 (M+H)⁺

Step 2: Preparation of4-benzyloxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P3.5)

To a solution of4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(40.0 g, 98.4 mmol) in tetrahydrofuran (500 ml) at 0° C. was added a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (108.3ml, 108.3 mmol) dropwise over one hour. The mixture was stirred at 0° C.for 30 minutes and at room temperature for 30 minutes, then treated withmethyl iodide (6.75 ml, 15.4 g, 108.2 mmol) dropwise at 0° C. over 10minutes. Stirring was continued at room temperature overnight and thereaction mixture was quenched with cold saturated aqueous ammoniumchloride. The layers were separated, the aqueous phase extracted twicewith ethyl acetate, the combined organic phases washed with brine, driedover sodium sulfate and concentrated. The residue was suspended indiethyl ether, stirred for 30 minutes, filtered and dried. Yield: 28.6 gof4-benzyloxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P3.5) as a solid, mp 139-141° C.

¹H-NMR (CDCl₃): 1.52 (br m, 1H), 1.74 (br m, 1H), 2.11 (br s, 6H), 2.28(s, 3H), 2.34 (br m, 2H), 2.92 (br signal, 3H), 3.12 (br m, 1H), 3.30(m, 3H), 3.52 (s, 3H), 4.67 (br signal, 2H), 6.85 (s, 2H), 7.04 (m, 2H),7.28 (m, 3H).

LC/MS (ES+): 421 (M+H)⁺

Step 3: Preparation of4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2.2)

To a solution of4-benzyloxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(22.6 g, 53.7 mmol) in methanol (226 ml) and water (22.6 ml) in a Parrshaker type hydrogenator was added 5% Pd/C (22.6 g). After hydrogenationunder 4 bars H₂ at 36° C. for 22 hours, the reaction mixture wasfiltered and concentrated. The residue was diluted with ethyl acetateand extracted with saturated aqueous sodium carbonate under ice cooling.The organic layer was discarded, the aqueous alkaline phase acidifiedwith cooling to pH 5-6 with an aqueous HCl solution and thoroughlyextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate and concentrated. Yield: 13.0 g of4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2.2) as a solid, mp 239-241° C. The spectral data wereidentical to those described above under preparation example 1, step 1.

EXAMPLE 3 Preparation of1-Cyclopropylmethyl-4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2.8) Step 1: Preparation of4-benzyloxy-1-cyclopropylmethyl-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P3.8)

To a solution of4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P3.4) (1.0 g, 2.46 mmol) in dioxane (40 ml) was addedbromomethyl-cyclopropane (1.257 ml, 1.78 g, 13.16 mmol) and potassiumtert-butoxide (1.50 g, 13.37 mmol). The reaction mixture was stirred at100° C. for 5 days, then poured on water and extracted with ethylacetate. The combined organic phases were washed with brine, dried oversodium sulfate and concentrated. The residue was suspended in ethylacetate/heptane 1:5, stirred overnight, filtered and dried to afford afirst crop of product as a white solid (350 mg). The mother liquor wasconcentrated, and the residue purified by chromatography on silica gel(dichloromethane/acetone 10:1) to further deliver 205 mg of product.Yield: 555 mg of4-benzyloxy-1-cyclopropylmethyl-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P3.8) as a solid, mp 119-121° C.

¹H-NMR (CD₃OD): 0.34 (m, 2H), 0.52 (m, 2H), 1.10 (m, 1H), 1.48 (br m,1H), 1.83 (br m, 1H), 2.11 (br s, 6H), 2.29 (s, 3H), 2.41 (br m, 1H),2.60 (br m, 1H), 3.12 (br m, 1H), 3.23 (m, 2H), 3.24-3.41 (br signals,total 3H), 3.50 (s, 3H), 4.72 (br signal, 2H), 6.91 (s, 2H), 7.06 (m,2H), 7.29 (m, 3H).

LC/MS (ES+): 461 (M+H)⁺

Step 2: Preparation of1-cyclopropylmethyl-4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2.8)

Debenzylation was conducted using an H-Cube® continuous-flowhydrogenator:4-benzyloxy-1-cyclopropylmethyl-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(546 mg, 1.34 mmol) was dissolved in methanol (47 ml) and this substratesolution (0.029 M) pumped twice through a 5% Pd/C filled cartridge at aflow-rate of 1 mL/min, a temperature of 35° C. and a pressure of 2-3bars. The collected product solution was concentrated, and the residuepurified by chromatography on silica gel (ethyl acetate/heptane 1:1).Yield: 215 mg of1-cyclopropylmethyl-4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2.8) as a white solid, mp 223-225° C.

¹H-NMR (CD₃OD): 0.34 (m, 2H), 0.52 (m, 2H), 1.11 (m, 1H), 1.43 (br m,1H), 1.78 (br m, 1H), 2.11 (s, 6H), 2.25 (s, 3H), 2.41 (br m, 1H), 2.62(br m, 1H), 3.23 (br signal, total 3H), 3.28-3.45 (br signals, total3H), 3.55 (s, 3H), 6.90 (s, 2H).

LC/MS (ES+): 371 (M+H)⁺, 369 (M−H)⁻

EXAMPLE 4 Preparation of4-Hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2.2) Step 1: Preparation of1-methoxy-4-methylamino-piperidine-4-carbonitrile (compound P5.1)

To a solution of 1-methoxy-piperidin-4-one [prepared according toJournal of Organic Chemistry (1961), 26, 1867-74] (100 g, 0.77 mol),aqueous methylamine (40 wt. % in H₂O, 86 ml) and methylaminehydrochloride (57.5 g, 0.85 mol) in water (700 ml) at 0° C. was added asolution of potassium cyanide (55.5 g, 0.85 mol) in water (150 ml)dropwise over one hour. The reaction mixture was stirred at roomtemperature for two days. Over the next five days, the mixture wasfurther treated with methylamine hydrochloride (5×2.6 g, total 13.0 g),aqueous methylamine (5×4.3 ml, total 21.5 ml) and potassium cyanide(5×2.5 g, total 12.5 g), and stirring continued at room temperatureuntil the reaction was judged complete by thin layer chromatography. Theaqueous reaction mixture was extracted with dichloromethane (lx 500 ml,and 4×200 ml), the combined organic phases dried over sodium sulfate andevaporated. Yield: 113.0 g of1-methoxy-4-methylamino-piperidine-4-carbonitrile (compound P5.1) as ared liquid. This material was used without further purification in thenext step.

¹H-NMR (CDCl₃): 1.36 (br s, 1H), 1.62-2.22 (br signals, total 4H), 2.51(s, 3H), 2.63-3.41 (br signals, total 4H), 3.51 (s, 3H).

IR(CN): ν 2220 cm⁻¹. LC/MS (ES+): 170 (M+H)⁺

Step 2: Preparation ofN-(4-cyano-1-methoxy-piperidin-4-yl)-N-methyl-2-(2,4,6-trimethyl-phenyl)-acetamide(compound P4.1)

Method A:

To a solution of 1-methoxy-4-methylamino-piperidine-4-carbonitrile (20.0g, 118.2 mmol), triethylamine (24.6 ml, 17.9 g, 177.3 mmol) and4-dimethylaminopyridine (DMAP, 0.1 g) in tetrahydrofuran (250 ml) at0-5° C. was added a solution of (2,4,6-trimethyl-phenyl)-acetyl chloride(25.6 g, 130.0 mmol) in THF (25 ml) dropwise over 1.5 hour. The reactionmixture was stirred at room temperature for a total of three hours,during which it was further treated with (2,4,6-trimethyl-phenyl)-acetylchloride (5.4 g) and triethylamine (7 ml). The reaction mixture wasdiluted with ethyl acetate and water, the layers separated, the aqueousphase extracted twice with ethyl acetate, the combined organic phaseswashed twice with saturated aqueous sodium hydrogen carbonate and brine,dried over sodium sulfate and concentrated. The solid residue wassuspended in diethyl ether (500 ml), stirred overnight at roomtemperature, filtered and dried. Yield: 27.5 g ofN-(4-cyano-1-methoxy-piperidin-4-yl)-N-methyl-2-(2,4,6-trimethyl-phenyl)-acetamide(compound P4.1) as a white solid, mp 171-178° C. This material was usedwithout further purification in the next step.

¹H-NMR (CDCl₃): 2.01 (br m, 1H), 2.11 (br m, 1H), 2.20 (s, 6H), 2.25 (s,3H), 2.34 (br m, 1H), 2.57 (br m, 1H), 2.83 (br m, 1H), 3.12 (s, 3H),3.20 (br m, 1H), 3.34 (br m, 2H), 3.50 (br s, 3H), 3.66 (s, 2H), 6.85(s, 2H).

IR(CN): ν 2231 cm⁻¹. LC/MS (ES+): 330 (M+H)⁺

Method B:

To a solution of 1-methoxy-4-methylamino-piperidine-4-carbonitrile (20.0g, 118.2 mmol) in pyridine (250 ml) was added(2,4,6-trimethyl-phenyl)-acetyl chloride (25.6 g, 130.0 mmol) dropwiseat 0° C. The reaction mixture was stirred at 0° C. for one hour and atroom temperature overnight, poured on ice water and acidified to pH 7with an aqueous 2N HCl solution. The resulting thick precipitate wasfiltered, washed with cold water, dissolved in dichloromethane, driedover sodium sulfate and concentrated. The solid residue was suspended inhexane, stirred at room temperature, filtered and dried. Yield: 32.7 gofN-(4-cyano-1-methoxy-piperidin-4-yl)-N-methyl-2-(2,4,6-trimethyl-phenyl)-acetamide(compound P4.1) as a pale yellow solid, mp 175-177° C. The spectral dataof this material were identical to those described above underpreparation example 4, step 2, Method A.

Step 3: Preparation of1-methoxy-4-{methyl-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (compound P4.2)

To a suspension ofN-(4-cyano-1-methoxy-piperidin-4-yl)-N-methyl-2-(2,4,6-trimethyl-phenyl)-acetamide(106.0 g, 0.322 mol) in methanol (222 ml) at 15-20° C. was addedconcentrated sulfuric acid (85.7 ml, 157.8 g, 1.609 mol) dropwise over75 minutes and the reaction mixture was stirred at room temperature forone hour. The mixture was poured on ice (1 kg), stirred for one hour,then neutralised carefully with 30% aqueous sodium hydroxide to pH 5-5.5(external ice cooling). The thick pasty mixture was diluted with water(1000 ml) and filtered. The solid residue was washed with water andhexane, air-dried and further dried over phosphorus pentoxide undervacuum at 40° C. for two hours. In order to eliminate inorganicimpurities (sodium sulfate!), the solid material was diluted withdichloromethane (600 ml), washed with water (2×300 ml), the aqueousphases extracted once with dichloromethane, the combined organic phasesdried over sodium sulfate and evaporated. Yield: 85.4 g of1-methoxy-4-{methyl-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (compound P4.2) as a white solid, mp 133-135° C.

¹H-NMR (CDCl₃): 1.92 (br m, 1H), 2.04 (br m, 1H), 2.16 (s, 6H), 2.23 (s,3H), 2.27-2.49 (br m, 2H), 2.82 (br m, 2H), 3.14 (br m, 2H), 3.22 (br s,3H), 3.52 (s, 3H), 3.62 (br s, 5H), 6.82 (s, 2H).

LC/MS (ES+): 363 (M+H)⁺

Step 4: Preparation of4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2.2)

To a solution of1-methoxy-4-{methyl-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (85.0 g, 234.5 mmol) in dimethylformamide (800 ml) at0° C. was added sodium methoxide (38.0 g, 703.5 mmol) in four portionsand stirring continued at 0° C. for 30 minutes, then at room temperaturefor 1 hour. The reaction mixture was poured on ice and saturated aqueousammonium chloride, acidified to pH 5-6 with concentrated HCl andthoroughly extracted with ethyl acetate. The combined organic layerswere washed with water and brine, dried over sodium sulfate,concentrated and the residue dried in vacuo. Yield: 72.7 g of4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2.2) as a solid.

The spectral data of this crude material were identical to thosedescribed above under preparation example 1, step 1.

EXAMPLE 5 Preparation of4-Cyclopropylamino-1-methoxy-piperidine-4-carbonitrile (compound P5.2)

To a solution of cyclopropylamine (1.4 ml, 1.14 g, 20.0 mmol) inmethanol (20 ml) at 0° C. was added 1N hydrochloric acid (20 ml, 20.0mmol) dropwise and the mixture was stirred at room temperature for 30minutes. 1-Methoxy-piperidin-4-one [prepared according to Journal ofOrganic Chemistry (1961), 26, 1867-74] (2.58 g, 20.0 mmol), followed 10minutes later by potassium cyanide (1.3 g, 20.0 mmol) in water (10 ml)were then added dropwise at 0° C. The reaction mixture was warmed toroom temperature and stirred overnight, diluted with water and diethylether, the layers separated and the aqueous phase thoroughly extractedwith diethyl ether. The combined organic layers were washed with brine,dried over sodium sulfate and evaporated. Yield: 3.19 g of4-cyclopropylamino-1-methoxy-piperidine-4-carbonitrile (title compoundP5.2) as an oil. This material was used without further purification inthe next step.

¹H-NMR (CDCl₃): 0.42 (br m, 2H), 0.56 (m, 2H), 1.57-2.30 (br signals,total 5H), 2.31 (m, 1H), 2.63-3.41 (br signals, total 4H), 3.51 (br s,3H).

IR(CN): ν 2223 cm⁻¹. LC/MS (ES+): 196 (M+H)⁺

EXAMPLE 6 Preparation of 1-Methoxy-4-methylamino-piperidine-4-carboxylicacid methyl ester (compound P5.4) Step 1: Preparation of8-methoxy-1-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione (compoundP5.6)

To a solution of 1-methoxy-4-methylamino-piperidine-4-carbonitrile(compound P5.1) (10.0 g, 59.09 mmol) in dichloromethane (180 ml) wasadded chlorosulfonyl isocyanate (5.14 ml, 8.36 g, 59.05 mmol) dropwiseover 15 minutes at 20-30° C. The yellowish suspension was stirred atroom temperature for 30 minutes and concentrated to generate a paleyellow solid. This material was dissolved in aqueous 1N hydrochloricacid (180 ml), heated at reflux for one hour, cooled to 0° C. andacidified to pH 5.5 with an aqueous 4N NaOH solution. The aqueous phasewas extracted with ethyl acetate (4×), the combined organic layers werewashed with brine, dried over sodium sulfate and concentrated. Theresidue was purified by chromatography on silica gel (ethylacetate/heptane 1:1). Yield: 3.86 g of8-methoxy-1-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione (compoundP5.6) as a solid.

¹H-NMR (CDCl₃): 1.33-2.41 (br signals, total 4H), 2.86 (br s, 3H),3.09-3.42 (br signals, total 4H), 3.52 (br s, 3H), 7.76 (br s, 1H).

LC/MS (ES+): 214 (M+H)⁺

Step 2: Preparation of 1-methoxy-4-methylamino-piperidine-4-carboxylicacid methyl ester (title compound P5.4)

To a suspension of8-methoxy-1-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione (3.36 g,15.76 mmol) in water (100 ml) was added sodium hydroxide (0.63 g, 15.75mmol) and the mixture was heated in a microwave apparatus at 190° C. for30 minutes, at 200° C. for one hour and further at 210° C. for one houruntil judged complete by LC-MS analysis. The reaction mixture wasacidified to pH 3 (ice cooling) with an aqueous HCl solution,concentrated in vacuo, the solid residue taken up in warm methanol (40°C.), filtered and the filtrate evaporated. The residue was dried overphosphorus pentoxide at 40° C. overnight. Yield: 2.08 g of1-methoxy-4-methylamino-piperidine-4-carboxylic acid hydrochloride salt.

LC/MS (ES+): 189 (M+H)⁺ of the free base.

To a suspension of 1-methoxy-4-methylamino-piperidine-4-carboxylic acidhydrochloride salt (2.08 g, 9.26 mmol) in methanol (20 ml) at 0-5° C.was added thionyl chloride (2.41 ml, 3.97 g, 33.40 mmol) and thereaction mixture was heated at reflux for 7 days. After cooling, themixture was concentrated, the residue diluted with ice water andneutralised with aqueous sodium bicarbonate. The aqueous phase wasextracted with ethyl acetate (4×), the combined organic layers washedwith brine, dried over sodium sulfate and concentrated. The residue waspurified by chromatography on silica gel (gradient ethyl acetate→ethylacetate/methanol 20:1). Yield: 76 mg of1-methoxy-4-methylamino-piperidine-4-carboxylic acid methyl ester (titlecompound P5.4) as an oil.

¹H-NMR (CDCl₃): 1.46-2.33 (br signals, total 5H), 2.22 (br s, 3H),2.51-3.31 (br signals, total 4H), 3.51 (s, 3H), 3.72 (br s, 3H).

IR(COOMe): ν 1726 cm⁻¹. LC/MS (ES+): 203 (M+H)⁺

EXAMPLE 7 Preparation of3-(2-Chloro-4,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2.26)

To a solution of2-(2-chloro-4,5-dimethyl-phenyl)-N-(4-cyano-1-methoxy-piperidin-4-yl)-N-methyl-acetamide(compound P4.27) (1.15 g, 3.29 mmol) in methanol (˜3 ml) at 10° C. wasadded concentrated sulfuric acid (0.876 ml, 16.43 mmol) dropwise and thereaction mixture was stirred at room temperature overnight. Afterfurther treatment with concentrated sulfuric acid (0.876 ml, 16.43 mmol)and stirring at 80° C. overnight, additional concentrated sulfuric acid(0.876 ml, 16.43 mmol) was added and stirring continued at 90° C. overanother night. The mixture was poured on ice, neutralised carefully with30% aqueous sodium hydroxide to pH 5-6, the resulting precipitatefiltered and dried to afford a first crop of product as a beige solid(225 mg). The mother liquor was concentrated, and the residue purifiedby chromatography on silica gel (ethyl acetate) to further deliver 462mg of product as a yellowish solid. Yield: 687 mg of3-(2-chloro-4,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2.26) as a solid, mp 191-192° C.

¹H-NMR (CD₃Cl₃): 1.49-2.57 (br signals, total 4H), 2.20 (s, 3H), 2.21(s, 3H), 2.79-3.46 (br signals, total 4H), 3.00 (br s, 3H), 3.52 (br s,3H), 4.40 (br s, 1H), 6.87 (s, 1H), 7.16 (s, 1H).

LC/MS (ES+): 351/353 (M+H)⁺

EXAMPLE 8 Alternative preparation of4-Hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2.2)

To a solution of4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one[starting material (SM) prepared according to WO09/049,851] (500 mg,1.58 mmol) in tetrahydrofuran (20 ml) at 0° C. was added a 1.0 M lithiumbis(trimethylsilyl)amide solution in hexanes (3.32 ml, 3.32 mmol)dropwise over 15 minutes. The mixture was stirred one hour at 0° C.,treated with methyl iodide (0.099 ml, 225 mg, 1.59 mmol) dropwise over10 minutes, and further stirred at 0° C. for 30 minutes and at roomtemperature for one hour. The reaction mixture was quenched over coldsaturated aqueous ammonium chloride and extracted with tert-butyl methylether (3×), the combined organic phases washed with brine, dried oversodium sulfate and concentrated. The residue (210 mg) was suspended inhexane, stirred at room temperature for 10 minutes, filtered and dried.Yield: 171 mg of a clean mixture of starting material (SM) and4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2.2) as a beige solid.

¹H-NMR and LC-MS analysis of the crude material indicated a ˜1:2.5 ratioof this mixture SM/compound P2.2.

¹H-NMR (CD₃OD, selected signals only): 6.86 (s, 2H, H_(arom) SM), 6.89(s, 2H, H_(arom) compound P2.2); both signals in a ratio 1:2.6.

LC/MS (ES+): 317 (M+H)⁺; R_(t)=1.40 min for SM. LC/MS (ES+): 331 (M+H)⁺;R_(t)=1.46 min for compound P2.2. Both signals in a ratio 1:2.5considering UV peak areas at 220 nm.

EXAMPLE 9 Preparation of 2,2-Dimethyl-propionic acid8-methoxy-1-methyl-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1.31)

To a solution of4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2.2) (350 mg, 1.06 mmol) and triethylamine (0.221 ml, 160.7mg, 1.59 mmol) in tetrahydrofuran (10 ml) at 0° C. was added pivaloylchloride (0.143 ml, 140.1 mg, 1.16 mmol) dropwise. The suspension wasstirred at 0° C. for two hours. The reaction mixture was diluted withethyl acetate and water, the layers separated, the aqueous phaseextracted with ethyl acetate, the combined organic phases washed withbrine, dried over sodium sulfate and concentrated. The residue waspurified by chromatography on silica gel (ethyl acetate). Yield: 344 mgof 2,2-dimethyl-propionic acid8-methoxy-1-methyl-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1.31) as a colorless gum.

¹H-NMR (CDCl₃): 1.02 (br s, 9H), 1.46-2.51 (br signals, total 4H), 2.14(s, 6H), 2.23 (s, 3H), 2.70-3.46 (br signals, total 4H), 2.95 (br s,3H), 3.54 (s, 3H), 6.82 (s, 2H).

LC/MS (ES+): 415 (M+H)⁺

EXAMPLE 10 Preparation of4-{[2-(2,5-Dimethyl-phenyl)-acetyl]-methyl-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P4.46) Step 1: Preparation of1-methoxy-4-methylamino-piperidine-4-carboxylic acid (compound P5.7)

1-Methoxy-4-methylamino-piperidine-4-carbonitrile (compound P5.1) (3.0g, 17.73 mmol) was added in two portions to concentrated sulfuric acid(30 ml) at 0° C. After stirring for 20 minutes, a yellow solution wasobtained which was kept at room temperature overnight. The reactionmixture was carefully diluted with ice water (60 ml), heated at refluxfor 4 hours, then poured on ice (50 g) and neutralised with 25% aqueousammonia under cooling to pH 7-8. The reaction mixture was evaporated andthe white solid residue triturated with warm (40° C.) methanol (3×50ml), filtered and the combined methanol phases concentrated. The residuewas treated with toluene (3×50 ml) to remove water azeotropically untilconstant weight, then triturated with tetrahydrofuran, filtered anddried. Yield: 2.30 g of 1-methoxy-4-methylamino-piperidine-4-carboxylicacid (compound P5.7) as a white solid, mp>250° C.

¹H-NMR (D₂O): 1.73 (m, 1H), 2.02 (m, 2H), 2.32 (m, 1H), 2.54 (appar. d,3H), 2.69 (m, 1H), 2.99 (m, 1H), 3.18 (m, 1H), 3.33 (m, 1H), 3.49(appar. d, 3H). The spectral data are suggesting two major conformers ina 1:1 ratio.

LC/MS (ES+): 189 (M+H)⁺

Step 2: Preparation of 1-methoxy-4-methylamino-piperidine-4-carboxylicacid methyl ester (compound P5.4)

To a suspension of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid(2.0 g, 10.63 mmol) in methanol (50 ml) at 0-10° C. was added thionylchloride (2.29 ml, 3.76 g, 31.57 mmol) and the reaction mixture washeated at reflux overnight. After cooling, the mixture was concentrated,the residue diluted with ice water (20 ml) and neutralised with aqueoussodium bicarbonate. The aqueous phase was extracted with ethyl acetate(4×25 ml) and dichloromethane (4×50 ml), the combined organic layerswashed with aqueous sodium bicarbonate (15 ml) and brine (15 ml), driedover sodium sulfate and concentrated. Yield: 0.76 g of1-methoxy-4-methylamino-piperidine-4-carboxylic acid methyl ester(compound P5.4) as a viscous, orange oil. The spectral data of thiscrude material were identical to those described above under preparationexample 6, step 2.

LC/MS (ES+): 203 (M+H)⁺

Step 3: Preparation of4-{[2-(2,5-dimethyl-phenyl)-acetyl]-methyl-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (title compound P4.46)

To a solution of 1-methoxy-4-methylamino-piperidine-4-carboxylic acidmethyl ester (200 mg, 0.99 mmol) in pyridine (5 ml) was added(2,5-dimethyl-phenyl)-acetyl chloride (240 mg, 1.31 mmol) dropwise at 0°C. The reaction mixture was stirred at 0° C. for one hour and at roomtemperature for 6 hours, poured on ice water, acidified to pH 7 with anaqueous 2N HCl solution and diluted with ethyl acetate (50 ml). Thelayers were separated, the aqueous phase extracted with ethyl acetate(3×25 ml), the combined organic phases washed with water (3×15 ml) andbrine, dried over sodium sulfate and concentrated. The residue waspurified by chromatography on silica gel (cyclohexane/ethyl acetate2:1). Yield: 170 mg of4-{[2-(2,5-dimethyl-phenyl)-acetyl]-methyl-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (title compound P4.46) as a colorless gum.

¹H-NMR (CD₃OD): 1.99 (br m, 2H), 2.17 (s, 3H), 2.26 (s, 3H), 2.36 (br m,2H), 2.79 (br m, 1H), 2.93 (br m, 1H), 3.06 (appar. d, 3H), 3.21 (br m,2H), 3.50 (s, 3H), 3.67 (s, 3H), 3.68 (br s, 2H), 6.91 (br s, 1H), 6.95(d, 1H), 7.04 (d, 1H).

LC/MS (ES+): 349 (M+H)⁺

Compounds of the formula I from Table P1, compounds of the formula IIfrom Table P2 and intermediates listed in Tables P3, P4 and P5 can beprepared by analogous procedures. Either one of the following LC-MSmethods was used to characterize the compounds:

Method A

MS:

ZQ Mass Spectrometer from Waters (Single quadrupole mass spectrometer);Ionisation method: Electrospray; Polarity: positive/negative ions;Capillary (kV) 3.00, Cone (V) 30.00, Extractor (V) 2.00, SourceTemperature (° C.) 100, Desolvation Temperature (° C.) 250, Cone GasFlow (L/Hr) 50, Desolvation Gas Flow (L/Hr) 400; Mass range: 150 to 1000or 100 to 900 Da.

LC:

HP 1100 HPLC from Agilent: solvent degasser, quaternary pump(ZCQ)/binary pump (ZDQ), heated column compartment and diode-arraydetector. Column: Phenomenex Gemini C18, 3 μm particle size, 110Angstrom, 30×3 mm, Temp: 60° C.; DAD Wavelength range (nm): 200 to 500;Solvent gradient: A=water+0.05% v/v HCOOH, B=Acetonitril/Methanol (4:1,v/v)+0.04% v/v HCOOH.

Time (min) A % B % Flow (ml/min) 0.00 95.0 5.0 1.700 2.00 0.0 100.01.700 2.80 0.0 100.0 1.700 2.90 95.0 5.0 1.700 3.00 95.0 5.0 1.700

Method B

MS:

ZMD Mass Spectrometer from Waters (Single quadrupole mass spectrometer);Ionisation method: Electrospray; Polarity: positive/negative ions;Capillary (kV) 3.80, Cone (V) 30.00, Extractor (V) 3.00, SourceTemperature (° C.) 150, Desolvation Temperature (° C.) 350, Cone GasFlow (L/Hr) OFF, Desolvation Gas Flow (L/Hr) 600; Mass range: 150 to1000 (100 to 1500 for LowMass) or 100 to 900 Da.

LC:

HP 1100 HPLC from Agilent: solvent degasser, binary pump, heated columncompartment and diode-array detector. Column: Phenomenex Gemini C18, 3μm particle size, 110 Angstrom, 30×3 mm, Temp: 60° C.; DAD Wavelengthrange (nm): 200 to 500; Solvent gradient: A=water+0.05% v/v HCOOH,B=Acetonitril/Methanol (4:1, v:v)+0.04% v/v HCOOH.

Time (min) A % B % Flow (ml/min) 0.00 95.0 5.0 1.700 2.00 0.0 100.01.700 2.80 0.0 100.0 1.700 2.90 95.0 5.0 1.700 3.00 95.0 5.0 1.700

The characteristic values obtained for each compound were the retentiontime (“R_(t)”, recorded in minutes) and the molecular ion as listed inTable P1, Table P2, Table P3, Table P4 and in Table P5.

TABLE P1 Physical data of compounds of formula I: Compound Melting No.Structures Point MS/NMR P1.1

96-110° C. LC/MS: 389 (M + H)⁺ R_(t) = 1.82 min P1.2

134-136° C. LC/MS: 403 (M + H)⁺ R_(t) = 1.81 min P1.3

gum ¹H-NMR (CD3OD, selected signals only): 1.03 (t, 3H, OCH₂CH₃), 2.14(s, 6H, mesityl CH₃), 2.26 (s, 3H, mesityl CH₃), 3.34 (br s, 3H,CH₂OCH₃), 3.55 (s, 3H, NOCH₃), 4.01 (q, 2H, OCH₂CH₃), 6.89 (s, 2H,H_(arom)). P1.4

solid LC/MS: 447 (M + H)⁺ R_(t) = 1.94 min P1.5

gum ¹H-NMR (CD₃OD): 0.38 (m, 2H), 0.55 (m, 2H), 1.02 (t, 3H), 1.15 (m,1H), 1.54 (br m, 1H), 1.88 (br m, 1H), 2.13 (s, 6H), 2.25 (s, 3H), 2.48(br m, 1H), 2.66 (br m, 1H), 2.83 (br m, 1H), 3.18 (br m, 1H), 3.30 (brm, 2H), 3.41 (br m, 2H), 3.55 (s, 3H), 4.00 (q, 2H), 6.87 (s, 2H). LC/MS(ES+): 443 (M + H)⁺; R_(t) = 2.06 min P1.6

164-167° C. LC/MS: 423/425 (M + H)⁺ R_(t) = 1.82 min P1.7

gum LC/MS: 429 (M + H)⁺ R_(t) = 1.93 min P1.8

101-103° C. LC/MS: 417 (M + H)⁺ R_(t) = 1.91 min P1.9

solid LC/MS: 427/429 (M + H)⁺ R_(t) = 1.75 min P1.10

47-50° C. LC/MS: 427/429 (M + H)⁺ R_(t) = 1.73 min P1.11

163-167° C. LC/MS: 467/469 (M + H)⁺ R_(t) = 1.83 min P1.12

126-127° C. LC/MS: 467/469 (M + H)⁺ R_(t) = 1.89 min P1.13

106-109° C. LC/MS: 389 (M + H)⁺ R_(t) = 1.74 min P1.14

gum LC/MS: 471/473 (M + H)⁺ R_(t) = 1.81 min P1.15

87-89° C. LC/MS: 473/475/477 (M + H)⁺ R_(t) = 1.80 min P1.16

gum LC/MS: 461 (M + H)⁺ R_(t) = 1.91 min P1.17

gum LC/MS: 477 (M + H)⁺ R_(t) = 1.89 min P1.18

gum LC/MS: 477 (M + H)⁺ R_(t) = 1.91 min P1.19

solid LC/MS: 417 (M + H)⁺ R_(t) = 1.86 min P1.20

158-159° C. ¹H-NMR (CDCl₃, selected signals only): 1.16 (t, 3H,OCH₂CH₃), 2.20 (s, 3H, phenyl CH₃), 2.22 (s, 3H, phenyl CH₃), 2.94 (brs, 3H, N—CH₃; overlapping signal with piperidinyl Hs), 3.56 (s, 3H,NOCH₃), 4.09 (q, 2H, OCH₂CH₃), 7.07 (s, 1H, H_(arom)), 7.35 (s, 1H,H_(arom)). P1.21

gum LC/MS 403 (M + H)⁺ R_(t) = 1.81 min P1.22

149-150° C. LC/MS: 423/425 (M + H)⁺ R_(t) = 1.91 min P1.23

gum LC/MS: 403 (M + H)⁺ R_(t) = 1.83 min P1.24

solid LC/MS: 467/469 (M + H)⁺ R_(t) = 1.88 min P1.25

solid LC/MS: 389 (M + H)⁺ R_(t) = 1.77 min P1.26

gum LC/MS: 473 (M + H)⁺ R_(t) = 1.96 min P1.27

gum LC/MS: 423/425 (M + H)⁺ R_(t) = 1.84 min P1.28

gum LC/MS: 423/425 (M + H)⁺ R_(t) = 1.86 min P1.29

130-132° C. LC/MS: 423/425 (M + H)⁺ R_(t) = 1.86 min P1.30

LC/MS: 345 (M + H)⁺ R_(t) = 1.77 min P1.31

gum LC/MS: 415 (M + H)⁺ R_(t) = 2.00 min

TABLE P2 Physical data of compounds of formula II: Compound No.Structures Melting Point MS/NMR P2.1

121-123° C. LC/MS: 317 (M + H)⁺ R_(t) = 1.49 min P2.2

  EXAMPLE 1, step 1 EXAMPLE 2, step 3 EXAMPLE 4, step 4 241-243° C.LC/MS: 331 (M + H)⁺ R_(t) = 1.44 min P2.3

solid ¹H-NMR (400 MHz, CDCl₃): 1.75 (m, 2H), 2.31 (m, 2H), 2.48 (m, 2H),3.47 (m, 2H), 3.58 (s, 3H), 3.93 (m, 2H), 5.90 (m, 1H), 6.30 (br s, 1H),7.25-7.32 (m, 2H), 7.40 (m, 1H). P2.4

solid ¹H-NMR (400 MHz, CDCl₃, selected signals only): 3.57 (s, 3H,NOCH₃), 5.85 (m, 1H, CHF₂), 6.52 (br s, 1H), 7.27-7.35 (m, 2H,H_(arom)), 7.49 (d, 1H, H_(arom)). P2.5

solid ¹H-NMR (400 MHz, CDCl₃, selected signals only): 2.18 (s, 3H,phenyl CH₃), 2.31 (s, 3H, phenyl CH₃), 3.39 (s, 3H, NOCH₃), 5.78 (m, 1H,CHF₂), 6.19 (br s, 1H), 7.00 (s, 1H, H_(arom)), 7.08 (d, 1H, H_(arom)),7.12 (d, 1H, H_(arom)). P2.6

205-207° C. LC/MS: 361 (M + H)⁺ R_(t) = 1.47 min P2.7

solid LC/MS: 375 (M + H)⁺ R_(t) = 1.58 min P2.8

  EXAMPLE 3, step 2 223-225° C. LC/MS: 371 (M + H)⁺ R_(t) = 1.76 minP2.9

  >240° C. LC/MS: 351/353 (M + H)⁺ R_(t) = 1.48 min P2.10

208-211° C. LC/MS: 357 (M + H)⁺ R_(t) = 1.61 min P2.11

218-221° C. LC/MS: 345 (M + H)⁺ R_(t) = 1.58 min P2.12

solid LC/MS: 355/357 (M + H)⁺ R_(t) = 1.52 min P2.13

 54-57° C. LC/MS: 355/357 (M + H)⁺ R_(t) = 1.49 min P2.14

solid LC/MS: 395/397 (M + H)⁺ R_(t) = 1.48 min P2.15

191-195° C. LC/MS: 351/353 (M + H)⁺ R_(t) = 1.58 min P2.16

234-235° C. LC/MS: 395/397 (M + H)⁺ R_(t) = 1.54 min P2.17

202-204° C. LC/MS: 317 (M + H)⁺ R_(t) = 1.36 min P2.18

gum LC/MS: 399/401 (M + H)⁺ R_(t) = 1.54 min P2.19

 80-82° C. ¹H-NMR (CD3OD, selected signals only): 2.12 (s, 6H, mesitylCH₃), 2.27 (s, 3H, mesityl CH₃), 3.37 (s, 3H, CH₂CH₂OCH₃), 3.47 (t, 2H,CH₂CH₂OMe), 3.55 (s, 3H, NOCH₃), 3.65 (t, 2H, CH₂CH₂OMe), 6.91 (s, 2H,H_(arom)). P2.20

 79-81° C. LC/MS: 389 (M + H)⁺ R_(t) = 1.62 min P2.21

181-183° C. LC/MS: 405 (M + H)⁺ R_(t) = 1.60 min P2.22

solid LC/MS: 345 (M + H)⁺ R_(t) = 1.55 min P2.23

191-193° C. LC/MS: 395/397 (M + H)⁺ R_(t) = 1.59 min P2.24

192-194° C. LC/MS: 331 (M + H)⁺ R_(t) = 1.41 min P2.25

183-186° C. LC/MS: 331 (M + H)⁺ R_(t) = 1.56 min P2.26

  EXAMPLE 7 191-192° C. LC/MS: 351/353 (M + H)⁺ R_(t) = 1.60 min P2.27

138-142° C. LC/MS: 351/353 (M + H)⁺ R_(t) = 1.49 min P2.28

182-183° C. LC/MS: 395/397 (M + H)⁺ R_(t) = 1.62 min P2.29

solid LC/MS: 317 (M + H)⁺ R_(t) = 1.47 min P2.30

180-182° C. LC/MS: 401 (M + H)⁺ R_(t) = 1.50 min P2.31

gum LC/MS: 365/367 (M + H)⁺ R_(t) = 1.59 min P2.32

211-213° C. LC/MS: 401 (M + H)⁺ R_(t) = 1.60 min P2.33

solid LC/MS: 351/353 (M + H)⁺ R_(t) = 1.50 min P2.34

  >200° C. LC/MS: 415/417/419 (M + H)⁺ R_(t) = 1.54 min

Intermediates of the formula XIII or XIV from Table P3 can be preparedby analogous procedures.

TABLE P3 Physical data of intermediates of formula XIII or XIV: CompoundNo. Structures Melting Point MS/NMR P3.1

128-131° C. Described in WO09/049851 P3.2

180-183° C. Described in WO09/049851 P3.3

111-113° C. Described in WO09/049851 P3.4

  EXAMPLE 2, step 1 184-186° C. LC/MS: 407 (M + H)⁺ R_(t) = 2.02 minP3.5

  EXAMPLE 2, step 2 139-141° C. LC/MS: 421 (M + H)⁺ R_(t) = 2.04 minP3.6

solid LC/MS: 451 (M + H)⁺ R_(t) = 2.08 min P3.7

solid LC/MS: 465 (M + H)⁺ R_(t) = 2.05 min P3.8

  EXAMPLE 3, step 1 119-121° C. LC/MS: 461 (M + H)⁺ R_(t) = 2.19 minP3.9

134-136° C. LC/MS: 447 (M + H)⁺ R_(t) = 2.14 min P3.10

solid LC/MS: 435 (M + H)⁺ R_(t) = 2.07 min P3.11

 90-92° C. LC/MS: 495 (M + H)⁺ R_(t) = 2.06 min P3.12

 68-70° C. LC/MS: 495 (M + H)⁺ R_(t) = 2.05 min P3.13

solid LC/MS: 479 (M + H)⁺ R_(t) = 2.07 min P3.14

LC/MS: 491 (M + H)⁺ R_(t) = 2.04 min

Intermediates of the formula IV or XI from Table P4 can be prepared byanalogous procedures.

TABLE P4 Physical data of intermediates of formula IV or XI: CompoundNo. Structures Melting Point MS/NMR P4.1

  EXAMPLE 4, step 2 175-177° C. LC/MS: 330 (M + H)⁺ R_(t) = 1.78 minP4.2

  EXAMPLE 4, step 3 133-135° C. LC/MS: 363 (M + H)⁺ R_(t) = 1.79 minP4.3

LC/MS: 350/352 (M + H)⁺ R_(t) = 1.78 min P4.4

LC/MS: 383/385 (M + H)⁺ R_(t) = 1.79 min P4.5

LC/MS: 354/356 (M + H)⁺ R_(t) = 1.71 min P4.6

LC/MS: 387/389 (M + H)⁺ R_(t) = 1.73 min P4.7

LC/MS: 354/356 (M + H)⁺ R_(t) = 1.70 min P4.8

LC/MS: 387/389 (M + H)⁺ R_(t) = 1.71 min P4.9

LC/MS: 394/396 (M + H)⁺ R_(t) = 1.78 min P4.10

LC/MS: 427/429 (M + H)⁺ R_(t) = 1.81 min P4.11

LC/MS: 350/352 (M + H)⁺ R_(t) = 1.78 min P4.12

LC/MS: 383/385 (M + H)⁺ R_(t) = 1.78 min P4.13

solid LC/MS: 394/396 (M + H)⁺ R_(t) = 1.78 min P4.14

solid LC/MS: 427/429 (M + H)⁺ R_(t) = 1.80 min P4.15

171-174° C. LC/MS: 316 (M + H)⁺ R_(t) = 1.64 min P4.16

139-141° C. LC/MS: 349 (M + H)⁺ R_(t) = 1.64 min P4.17

gum LC/MS: 398/400 (M + H)⁺ R_(t) = 1.71 min P4.18

solid LC/MS: 431/433 (M + H)⁺ R_(t) = 1.75 min P4.19

¹H-NMR (CDCl₃, selected signals only): 3.15 (s, 3H, N—CH₃), 3.50 (br s,3H, NOCH₃), 3.75 (s, 2H, PhCH₂CO), 6.89 (s, 1H, H_(arom)). P4.20

LC/MS: 377 (M + H)⁺ R_(t) = 1.81 min P4.21

gum LC/MS: 427/429 (M + H)⁺ R_(t) = 1.82 min P4.22

123-126° C. LC/MS: 394/396 (M + H)⁺ R_(t) = 1.82 min P4.23

¹H-NMR (CDCl₃, selected signals only): 2.13 (s, 3H, phenyl CH₃), 2.22(s, 3H, phenyl CH₃), 2.25 (s, 3H, phenyl CH₃), 3.14 (s, 3H, N—CH₃), 3.51(br s, 3H, NOCH₃), 3.73 (s, 2H, PhCH₂CO). P4.24

¹H-NMR (CDCl₃, selected signals only): 3.52 (br s, 3H, NOCH₃). P4.25

LC/MS: 330 (M + H)⁺ R_(t) = 1.78 min P4.26

LC/MS: 363 (M + H)⁺ R_(t) = 1.77 min P4.27

solid LC/MS: 350/352 (M + H)⁺ R_(t) = 1.54 min P4.28

P4.29

P4.30

P4.31

134-136° C. LC/MS: 400 (M + H)⁺ R_(t) = 1.87 min P4.32

132-134° C. LC/MS: 433 (M + H)⁺ R_(t) = 1.87 min P4.33

144-146° C. LC/MS: 394/396 (M + H)⁺ R_(t) = 1.82 min P4.34

gum LC/MS: 427/429 (M + H)⁺ R_(t) = 1.84 min P4.35

solid LC/MS: 316 (M + H)⁺ R_(t) = 1.66 min P4.36

solid LC/MS: 349 (M + H)⁺ R_(t) = 1.67 min P4.37

188-192° C. LC/MS: 350/352 (M + H)⁺ R_(t) = 1.75 min P4.38

150-152° C. LC/MS: 383/385 (M + H)⁺ R_(t) = 1.77 min P4.39

solid LC/MS: 414/416/418 (M + H)⁺ R_(t) = 1.78 min P4.40

gum LC/MS: 447/449/451 (M + H)⁺ R_(t) = 1.82 min P4.41

LC/MS: 356 (M + H)⁺ R_(t) = 1.87 min P4.42

LC/MS: 389 (M + H)⁺ R_(t) = 1.89 min P4.43

gum LC/MS: 370 (M + H)⁺ R_(t) = 1.99 min P4.44

P4.45

P4.46

  EXAMPLE 10, step 3 gum LC/MS: 349 (M + H)⁺ R_(t) = 1.66 min

Intermediates of the formula V, VII, VIII or IX from Table P5 can beprepared by analogous procedures.

TABLE P5 Physical data of intermediates of formula V, VII, VIII or IX:Compound No. Structures Melting Point MS/NMR/IR P5.1

  EXAMPLE 4, step 1 liquid ¹H-NMR (CDCl₃): 1.36 (br s, 1H), 1.62-2.22(br signals, total 4H), 2.51 (s, 3H), 2.63-3.41 (br signals, total 4H),3.51 (s, 3H). LC/MS (ES+): 170 (M + H)⁺; R_(t) = 0.25 min P5.2

  EXAMPLE 5 LC/MS: 196 (M + H)⁺ R_(t) = 1.14 min IR (CN): v 2223 cm⁻¹P5.3

oil LC/MS: 240 (M + H)⁺ R_(t) = 1.18 min P5.4

  EXAMPLE 6, step 2 EXAMPLE 10, step 2 oil ¹H-NMR (CDCl₃): 1.46-2.33 (brsignals, total 5H), 2.22 (br s, 3H), 2.51- 3.31 (br signals, total 4H),3.51 (s, 3H), 3.72 (br s, 3H). LC/MS (ES+): 203 (M + H)⁺; R_(t) = 0.20min P5.5

LC/MS: 210 (M + H)⁺ R_(t) = 1.10 min IR (CN): v 2222 cm⁻¹ P5.6

  EXAMPLE 6, step 1 solid LC/MS: 214 (M + H)⁺ R_(t) = 0.75 min P5.7

  EXAMPLE 10, step 1 >250° C. ¹H-NMR (D₂O): 1.73 (m, 1H), 2.02 (m, 2H),2.32 (m, 1H), 2.54 (appar. d, 3H), 2.69 (m, 1H), 2.99 (m, 1H), 3.18 (m,1H), 3.33 (m, 1H), 3.49 (appar. d, 3H). LC/MS (ES+): 189 (M + H)⁺; R_(t)= 0.21 min

EXAMPLE 11 Preparation of Carbonic acid3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxy-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-ylester ethyl ester (compound P1ii.2) Step 1: Preparation of1-methoxy-piperidin-4-one oxime

To a solution of 1-methoxy-piperidin-4-one [prepared according toJournal of Organic Chemistry (1961), 26, 1867-74] (258 g, 2.0 mol) andtriethylamine (305.2 ml, 221.9 g, 4.4 mol) in methanol (3000 ml) wasadded hydroxylamine hydrochloride (277.6 g, 4.0 mol), and the reactionmixture heated at reflux for 1.5 hours. The solvent was evaporated, theresidue diluted with diethyl ether and the suspension filtered. Thefiltrate was washed with water and brine, dried over sodium sulfate andconcentrated. Yield: 286.25 g of 1-methoxy-piperidin-4-one oxime as acolorless, viscous oil. This material was used without furtherpurification in the next step.

¹H-NMR (CDCl₃): 2.2-3.45 (br signals, total 8H), 3.55 (s, 3H), 8.65 (brs, 1H).

LC/MS (ES+): 145 (M+H)⁺

Step 2: Preparation of4-hydroxyamino-1-methoxy-piperidine-4-carbonitrile (compound P4ii.1)

To a suspension of 1-methoxy-piperidin-4-one oxime (240 g, 1.66 mol) andpotassium dihydrogen phosphate (792.9 g, 5.83 mol) in water (200 ml) at0-5° C. was added a solution of potassium cyanide (195.1 g, 3.0 mol) inwater (200 ml) dropewise (caution!). The reaction mixture was stirred atroom temperature overnight (stoppered flask), treated with anotherportion of potassium dihydrogen phosphate (79.3 g, 0.58 mol) and furtherstirred at room temperature over another night. The mixture was flushedwith nitrogen, the semi-solid removed by filtration and dissolved inethyl acetate. The aqueous layer was extracted twice with ethyl acetate,all organic layers combined, washed with water and brine, dried oversodium sulfate and concentrated. The residue was triturated with colddiethyl ether, filtered and dried. Yield: 230.8 g of4-hydroxyamino-1-methoxy-piperidine-4-carbonitrile as a tan solid, mp130-131° C.

¹H-NMR (CDCl₃): 1.55-2.35 (br signals, total 4H), 2.60-3.45 (br signals,total 4H), 3.52 (s, 3H), 5.19 (br s, 1H), 5.42 (br s, 1H).

IR(CN): ν 2227.8 cm⁻¹. LC/MS (ES+): 172 (M+H)⁺

Step 3: Preparation of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound 4ii.2)

To a suspension of 4-hydroxyamino-1-methoxy-piperidine-4-carbonitrile(230 g, 1.34 mol) in dichloromethane (2400 ml) at room temperature wasadded concentrated sulfuric acid (358 ml, 658.8 g, 6.72 mol) dropewise,and the reaction mixture was stirred at 40° C. for one hour. Methanol(925.1 ml, 731.7 g, 22.8 mol) was added at 40° C. dropewise, and themixture stirred at 40° C. for 4 hours. The dichloromethane was distilledoff allowing to heat the reaction mixture at 60° C. for 24 hours. Thereaction mixture was poured on ice (3 kg) and neutralized by carefuladdition of concentrated aqueous sodium hydroxide first, followed bysaturated aqueous sodium hydrogen carbonate. The aqueous phase wassaturated with sodium chloride, extracted with ter-butyl methyl ether(10×300 ml), the combined organic layers washed with brine, dried oversodium sulfate and concentrated to afford a first crop of product (163.8g). Further extraction of the aqueous layer with ethyl acetate deliveredanother 35 g of crude product. Yield: 198.8 g of4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid methyl ester as ared-brown, viscous oil. This material was used without furtherpurification in the next step.

¹H-NMR (CDCl₃): 1.50-2.40 (br signals, total 4H), 2.76 (br m, 2H),3.01-3.32 (br m, 2H), 3.52 (s, 3H), 3.76 (s, 3H), 5.58 (br s, 2H).

IR(COOMe): ν 1731.3 cm⁻¹. LC/MS (ES+): 205 (M+H)⁺

Step 4: Preparation of4-{[2-(2,5-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.1)

To a solution of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acidmethyl ester (50 g, 244.8 mmol) in tetrahydrofuran (500 ml) at 0° C. wasadded sodium hydrogen carbonate (34.96 g, 416.2 mmol), followed by asolution of (2,5-dimethyl-phenyl)-acetyl chloride [prepared by treatment(2,5-dimethyl-phenyl)-acetic acid with oxalyl chloride indichloromethane under standard conditions] (44.72 g, 244.8 mmol) intetrahydrofuran (500 ml) dropwise. The reaction mixture was stirred at0° C. for one hour and at room temperature for two hours. The solventwas evaporated, the residue diluted with water and ethyl acetate and thelayers separated. The aqueous phase was extracted with ethyl acetate(6×250 ml), the combined organic layers washed with an aqueous sodiumhydrogen carbonate solution and brine, dried over sodium sulfate andconcentrated. The crude product was triturated with a cold diethylether/hexane 1:1 solution, filtered and dried to afford 36.4 g as awhite solid. The mother liquor was concentrated and purified bychromatography on silica gel (ethyl acetate/hexane 1:1) to furtherafford 4.2 g of product. Yield: 40.6 g of4-{[2-(2,5-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.1), mp 137-139° C.

¹H-NMR (CDCl₃): 1.99-3.32 (br signals, total 8H), 2.23 (s, 3H), 2.29 (s,3H), 3.53 (s, 3H), 3.72 (s, 3H), 3.83 (s, 2H), 6.43 (br s, 1H), 6.98 (d,1H), 6.99 (s, 1H), 7.06 (d, 1H).

LC/MS (ES+): 351 (M+H)⁺

Step 5: Preparation of3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.2) [Two-Steps (Hydroxamic Acid O-Alkylation andCyclisation), One-Pot Procedure]

To a solution of4-{[2-(2,5-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (35 g, 100.0 mmol) in dimethylformamide (300 ml) at 0°C. was added sodium hydride (5.02 g, 55% w/w dispersion in mineral oil,115.0 mmol) in 5 portions. The reaction mixture was stirred at 0° C. for30 minutes, treated with chloromethyl methyl ether (8.96 ml, 9.5 g,118.0 mmol) dropwise, and further stirred at 0° C. for one hour and atroom temperature for 1.5 hours. To the mixture recooled at 0° C. wasadded sodium methoxide (8.1 g, 150 mmol) in one portion, and stirringcontinued at room temperature for 2.5 hours. The reaction mixture waspoured on ice water (500 ml), acidified to pH 5-6 with an aqueous HClsolution and thoroughly extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate andconcentrated. The crude oily product was triturated with a cold diethylether/hexane 1:1 solution, filtered and dried to afford 15.8 g as awhite solid. The mother liquor was concentrated and purified bychromatography on silica gel (ethyl acetate/hexane 2:1) to furtherafford 2.1 g of product. Yield: 17.9 g of3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.2), mp 136-138° C.

¹H-NMR (CDCl₃): 1.44-2.72 (br signals, total 4H), 2.27 (s, 3H), 2.30 (s,3H), 2.78-3.48 (br signals, total 4H), 3.59 (s, 3H), 3.64 (s, 3H), 4.41(s, 1H), 5.12 (br m, 2H), 6.76 (s, 1H), 7.02 (d, 1H), 7.10 (d, 1H)(mixture of keto-enol tautomers, signals of major diketo-form isomershown).

LC/MS (ES+): 363 (M+H)⁺, LC/MS (ES−): 361 (M−H)⁻

Step 6: Preparation of carbonic acid3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxy-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-ylester ethyl ester (title compound P1ii.2)

To a solution of3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(9.0 g, 24.83 mmol), triethylamine (6.9 ml, 5.0 g, 49.66 mmol) and4-dimethylaminopyridine (100 mg, 0.82 mmol) in tetrahydrofuran (250 ml)at 0° C. was added a solution of ethyl chloroformate (3.09 ml, 3.5 g,32.28 mmol) in tetrahydrofuran (20 ml) dropwise. The suspension wasstirred at 0° C. for one hour, and at room temperature for one hour. Thereaction mixture was evaporated, diluted with ethyl acetate and filteredto remove salts. The filtrate was washed with a saturated aqueous sodiumhydrogen carbonate solution (2×100 ml) and brine, dried over sodiumsulfate and concentrated. The oily residue was purified bychromatography on silica gel (ethyl acetate/hexane 1:1). Yield: 9.63 gof carbonic acid3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxy-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-ylester ethyl ester (title compound P1ii.2) as a white solid, mp 109-111°C.

¹H-NMR (CDCl₃): 1.06 (t, 3H), 1.75-2.05 (br m, 2H), 2.20 (s, 3H), 2.28(s, 3H), 2.47 (br m, 2H), 2.89 (br m, 1H), 3.15-3.45 (br m, 3H), 3.59(s, 3H), 3.64 (s, 3H), 3.99 (q, 2H), 5.07 (br s, 2H), 6.96 (s, 1H), 7.03(d, 1H), 7.09 (d, 1H).

LC/MS (ES+): 435 (M+H)⁺

EXAMPLE 12 Preparation of4-Hydroxy-8-methoxy-1-prop-2-ynyloxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.8) (stepwise hydroxamic acid O-alkylation andcyclisation) Step 1: Preparation of1-methoxy-4-{prop-2-ynyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (compound P3ii.4)

To a solution of4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.3 obtained in analogy to preparationexample 11, step 4) (500 mg, 1.37 mmol) in tetrahydrofuran (3 ml) at 0°C. was added sodium hydride (66 mg, 55% w/w dispersion in mineral oil,1.51 mmol) in 2 portions. The reaction mixture was stirred at 0° C. forone hour, treated with propargyl bromide (202 mg, 1.65 mmol) dropwise,and further stirred at room temperature overnight. The reaction mixturewas evaporated, diluted with ethyl acetate and filtered to remove salts.The filtrate was washed twice with brine, dried over sodium sulfate andconcentrated. The oily residue was purified by chromatography on silicagel (ethyl acetate/hexane 1:2). Yield: 321 mg of1-methoxy-4-{prop-2-ynyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (compound P3ii.4) as a colorless gum.

¹H-NMR (CDCl₃): 1.90-3.34 (br signals, total 8H), 2.21 (s, 6H), 2.24 (s,3H), 2.68 (t, 1H), 3.53 (s, 3H), 3.68 (s, 3H), 3.77 (d, 1H), 4.03 (m,1H), 4.65-4.89 (br m, 2H), 6.84 (s, 2H).

LC/MS (ES+): 403 (M+H)⁺

Step 2: Preparation of4-hydroxy-8-methoxy-1-prop-2-ynyloxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2ii.8)

To a solution of1-methoxy-4-{prop-2-ynyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (150 mg, 0.41 mmol) in dimethylformamide (2 ml) at 0°C. was added sodium methoxide (33 mg, 0.62 mmol) in one portion andstirring continued at room temperature for 4 hours. The reaction mixturewas poured on ice water, acidified to pH 5-6 with an aqueous HClsolution, saturated with sodium chloride and thoroughly extracted withethyl acetate. The combined organic layers were washed with brine, driedover sodium sulfate and concentrated. The residue was purified bychromatography on silica gel (ethyl acetate/hexane 2:1). Yield: 14 mg of4-hydroxy-8-methoxy-1-prop-2-ynyloxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2ii.8) as a tan solid.

¹H-NMR (CD₃OD): 1.97-2.08 (m, 2H), 2.10 (s, 6H), 2.25 (s, 3H), 2.23-2.32(m, 2H), 3.04 (br s, 1H), 3.20 (m, 2H), 3.38 (m, 2H), 3.54 (s, 3H), 4.76(br s, 2H), 6.89 (s, 2H).

LC/MS (ES+): 371 (M+H)⁺

EXAMPLE 13 Preparation of Carbonic acid ethyl ester8-methoxy-2-oxo-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1 ii.9) Step 1: Preparation of carbonic acid ethylester1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1ii.11)

To a solution of carbonic acid ethyl ester8-methoxy-1-methoxymethoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1 ii.7 obtained in analogy to preparation example 11,step 6) (1.0 g, 2.23 mmol) in bromotrimethylsilane (4.33 ml, 5.12 g,33.44 mmol) under argon atmosphere was added 3 {acute over (Å)}molecular sieves (0.5 g) and the reaction mixture was stirred at 75° C.overnight. The mixture was diluted with dichloromethane, filtered, thefiltrate evaporated, the residue triturated with cold diethyl ether,filtered and dried. The crude product was purified by chromatography onsilica gel (gradient dichloromethane→dichloromethane/methanol20:1→10:1). Yield: 580 mg of carbonic acid ethyl ester1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1ii.11) as a white solid, mp 154-155° C.

¹H-NMR (CD₃OD): 1.03 (t, 3H), 2.03 (br m, 2H), 2.13 (s, 6H), 2.22 (br m,2H), 2.25 (s, 3H), 2.94 (br m, 1H), 3.28 (br m, 2H), 3.44 (br m, 1H),3.54 (s, 3H), 4.00 (q, 2H), 6.87 (s, 2H).

LC/MS (ES+): 405 (M+H)⁺

Step 2: Preparation of carbonic acid ethyl ester8-methoxy-2-oxo-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (title compound P1 ii.9)

To a solution of carbonic acid ethyl ester1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (150 mg, 0.37 mmol) in dichloromethane (3 ml) under argonatmosphere was added 2,3-dihydro-furan (56 μl, 52 mg, 0.74 mmol) and acatalytic amount of p-toluenesulfonic acid monohydrate (2 mg). Thereaction mixture was stirred at room temperature for 4 hours, dilutedwith dichloromethane, washed twice with brine, dried over sodium sulfateand concentrated. The residue was purified by chromatography on silicagel (ethyl acetate/hexane 2:1). Yield: 114 mg of carbonic acid ethylester8-methoxy-2-oxo-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (title compound P1ii.9) as a colorless gum.

¹H-NMR (CD₃OD): 1.02 (t, 3H), 1.70-2.22 (br signals, total 6H), 2.12 (s,3H), 2.13 (s, 3H), 2.25 (s, 3H), 2.31-2.68 (br m, 2H), 2.86 (br m, 1H),3.20 (br m, 1H), 3.39 (br m, 2H), 3.54 (s, 3H), 3.96 (m, 1H), 4.00 (q,2H), 4.18 (q, 1H), 5.62 (br s, 1H), 6.88 (s, 2H).

LC/MS (ES+): 475 (M+H)⁺

EXAMPLE 14 Preparation of1,4-Dihydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.4)

To a solution of4-hydroxy-8-methoxy-1-methoxymethoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.6 obtained in analogy to preparation example 11, step 5)(500 mg, 1.33 mmol) in dichloromethane (10 ml) under argon atmosphere at0° C. was added 3 {acute over (Å)} molecular sieves (0.5 g), followed bybromotrimethylsilane (1.72 ml, 2.03 g, 13.28 mmol) dropewise and thereaction mixture was stirred at 0° C. for one hour and at roomtemperature for 48 hours. The mixture was poured on cold water, thewater layer saturated with sodium chloride and thoroughly extracted withdichloromethane. The combined organic layers were washed with brine,dried over sodium sulfate and concentrated. The residue was purified bychromatography on silica gel (ethyl acetate). Yield: 40 mg of1,4-dihydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2ii.4) as a white solid, mp 152-154° C.

¹H-NMR (CDCl₃): 1.82-2.58 (br signals, total 4H), 2.12 (s, 6H), 2.27 (s,3H), 2.93-3.46 (br signals, total 4H), 3.57 (br s, 3H), 6.89 (s, 2H),9.97 (br s, 1H).

LC/MS (ES+): 333 (M+H)⁺

EXAMPLE 15 Preparation of Carbonic acid ethyl ester8-methoxy-1-methoxycarbonyloxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1ii.13)

To a solution of carbonic acid ethyl ester1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (preparation example 13, step 1; compound P1ii.11) (140 mg, 0.33mmol), triethylamine (93 ut, 68 mg, 0.67 mmol) and4-dimethylaminopyridine (2 mg) in tetrahydrofuran (3 ml) at 0° C. wasadded a solution of methyl chloroformate (33 μl, 41 mg, 0.43 mmol) intetrahydrofuran (2 ml) dropwise. The suspension was stirred at 0° C. forone hour, and at room temperature for one hour. The reaction mixture wasevaporated, diluted with ethyl acetate and filtered to remove salts. Thefiltrate was washed with a saturated aqueous sodium hydrogen carbonatesolution (2×15 ml) and brine, dried over sodium sulfate andconcentrated. The oily residue was purified by chromatography on silicagel (ethyl acetate/hexane 1:2). Yield: 30 mg of carbonic acid ethylester8-methoxy-1-methoxycarbonyloxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (title compound P1ii.13) as a colorless gum.

¹H-NMR (CDCl₃): 1.06 (t, 3H), 2.16 (s, 6H), 2.20 (m, 4H), 2.25 (s, 3H),2.75-3.16 (br m, total 2H), 3.34 (br m, 2H), 3.55 (s, 3H), 3.96 (s, 3H),3.99 (q, 2H), 6.85 (s, 2H).

LC/MS (ES+): 463 (M+H)⁺

EXAMPLE 16 Alternative preparation of4-{[2-(2,5-Dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.1) Step 1: Preparation ofN-(4-cyano-1-methoxy-piperidin-4-yl)-2-(2,5-dimethyl-phenyl)-N-hydroxy-acetamide(compound P3ii.2)

To a solution of 4-hydroxyamino-1-methoxy-piperidine-4-carbonitrile(preparation example 11, step 2) (4.0 g, 23.4 mmol) and sodium hydrogencarbonate (3.0 g, 35.7 mmol) in ethyl acetate (35 ml) and water (25 ml)at 0° C. was added a solution of (2,5-dimethyl-phenyl)-acetyl chloride(4.2 g, 23.0 mmol) in ethyl acetate (35 ml) dropwise over one hour. Thereaction mixture was stirred at 0° C. for one hour and at roomtemperature for two hours. The layers of the biphasic system wereseparated, the aqueous phase extracted with ethyl acetate (3×), thecombined organic layers washed with brine, dried over sodium sulfate andconcentrated. The oily residue was purified by chromatography on silicagel (gradient ethyl acetate/hexane 1:2→1:1→2:1). Yield: 1.55 g ofN-(4-cyano-1-methoxy-piperidin-4-yl)-2-(2,5-dimethyl-phenyl)-N-hydroxy-acetamide(compound P3ii.2) as a white solid, mp 153-156° C.

¹H-NMR (CDCl₃): 2.11 (br m, 2H), 2.21 (s, 3H), 2.28 (s, 3H), 2.56 (br m,2H), 2.77 (br m, 1H), 3.10 (br m, 2H), 3.31 (br m, 1H), 3.50 (s, 3H),3.77 (s, 2H), 6.83 (br s, 1H), 6.97 (s, 1H), 6.98 (d, 1H), 7.06 (d, 1H).

IR(CN): ν 2238.0 cm⁻¹. LC/MS (ES+): 318 (M+H)⁺

Step 2: Preparation of4-{[2-(2,5-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (title compound P3ii.1)

To a solution ofN-(4-cyano-1-methoxy-piperidin-4-yl)-2-(2,5-dimethyl-phenyl)-N-hydroxy-acetamide(1.5 g, 4.73 mmol) in methanol (15 ml) at 0° C. was added concentratedsulfuric acid (1.26 ml, 2.3 g, 23.64 mmol) slowly dropwise and thereaction mixture was stirred at reflux for 40 hours. The mixture waspoured on ice (50 g), neutralized carefully with a saturated aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate(5×). The combined organic layers were washed with brine, dried oversodium sulfate and concentrated. The oily residue was purified bychromatography on silica gel (ethyl acetate/hexane 2:1) to afford 136 mgof an off-white solid. This material was triturated with a tert-butylmethyl ether/hexane 1:4 solution (2-3 ml), filtered and dried. Yield: 82mg of4-{[2-(2,5-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (title compound P3ii.1) as a white solid, mp 140-142°C.

The spectral data were identical to those described above underpreparation example 11, step 4.

EXAMPLE 17 Preparation of4-Hydroxy-8-methoxy-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.18) Stepwise Hydroxamic Acid O-Tetrahydrofuranylation andCyclisation) Step 1: Preparation of1-methoxy-4-{(tetrahydro-furan-2-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (compound P3ii.6)

To a solution of4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.3 obtained in analogy to preparationexample 11, step 4) (70 g, 192.1 mmol) in dichloromethane (1500 ml)under argon atmosphere was added 2,3-dihydro-furan (29.1 ml, 26.9 g,384.1 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate(1.94 g, 19.2 mmol). The reaction mixture was stirred at reflux for 7hours, filtered and concentrated. The residue was triturated withhexane, filtered and the solid dried in vacuo. Yield: 70.0 g of1-methoxy-4-{(tetrahydro-furan-2-yloxy)-[2-(2,4,6-trimethyl-phenyl)acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (compound P3ii.6) as a solid, mp 107-109° C. Thismaterial was used without further purification in the next step.

¹H-NMR (CD₃OD): 1.79-2.36 (br signals, total 6H), 2.15 (br s, 6H), 2.21(s, 3H), 2.42 (m, 1H), 2.65 (m, 1H), 2.80 (m, 1H), 3.10 (m, 1H), 3.26(br m, 2H), 3.53 (s, 3H), 3.63 (s, 3H), 3.77 (m, 1H), 4.01 (m, 1H), 4.10(m, 2H), 5.68 (br m, 1H), 6.80 (s, 2H).

LC/MS (ES+): 435 (M+H)⁺

Step 2: Preparation of4-hydroxy-8-methoxy-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2ii.18)

To a solution of1-methoxy-4-{(tetrahydro-furan-2-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (70 g, 161.1 mmol) in dimethylformamide (350 ml) at10° C. was added sodium methoxide (26.9 g, 483.3 mmol) in four portionsand stirring continued at 10° C. for 30 minutes, then at roomtemperature for 2 hours. The reaction mixture was poured on coldsaturated aqueous ammonium chloride and thoroughly extracted with ethylacetate (6×100 ml). The combined organic layers were washed with brine,dried over sodium sulfate, concentrated and dried in vacuo. The residuewas triturated with hexane, filtered and the solid dried. Yield: 51.0 gof4-hydroxy-8-methoxy-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2ii.18) as a tan solid, mp 144-146° C.

¹H-NMR (CD₃OD): 1.75-2.19 (br signals, total 6H), 2.11 (s, 6H), 2.24 (s,3H), 2.28-2.55 (m, 2H), 3.13-3.30 (m, 2H), 3.30-3.48 (m, 2H), 3.54 (s,3H), 3.92 (m, 1H), 4.17 (m, 1H), 5.58 (m, 1H), 6.87 (s, 2H).

LC/MS (ES+): 403 (M+H)⁺

EXAMPLE 18 Preparation of1-Cyclohexyloxy-4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.26) Stepwise Hydroxamic Acid O-Alkylation Via Mitsunobuand Cyclisation Step 1: Preparation of4-{cyclohexyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.8)

To a solution of triphenylphosphine (0.81 g, 3.09 mmol) in THF (20 ml)at 0° C. was added diisopropyl azodicarboxylate (0.64 ml, 0.66 g, 3.10mmol) dropwise and the resulting precipitate was stirred at 0° C. for 30minutes.4-{Hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.3 obtained in analogy to preparationexample 11, step 4) (1.0 g, 2.74 mmol) was further added in one portion,followed by a solution of cyclohexanol (0.33 ml, 0.31 g, 3.10 mmol) inTHF (2 ml) dropwise at 0° C. The reaction mixture was stirred at roomtemperature for two hours and concentrated in vacuo. The residue waspurified by chromatography on silica gel (ethyl acetate/cyclohexane1:3). Yield: 690 mg of4-{cyclohexyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.8) as a colorless gum.

¹H-NMR (CD₃OD): 1.17-1.59 (br signals, total 7H), 1.68 (m, 1H), 1.91 (m,2H), 2.03 (m, 1H), 2.17 (br s, 6H), 2.21 (s, 3H), 2.32 (m, 2H), 2.44 (m,1H), 2.69 (m, 1H), 3.09 (m, 1H), 3.25 (m, 2H), 3.51 (s, 3H), 3.61 (s,3H), 3.69 (m, 1H), 3.92-4.12 (m, 2H), 6.80 (s, 2H).

LC/MS (ES+): 447 (M+H)⁺

Step 2: Preparation of1-cyclohexyloxy-4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2ii.26)

To a solution of4-{cyclohexyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (600 mg, 1.34 mmol) in dimethylformamide (10 ml) at 0°C. was added sodium methoxide (217 mg, 4.02 mmol) in one portion and themixture was stirred at room temperature overnight. The reaction mixturewas poured on cold saturated aqueous ammonium chloride and thoroughlyextracted with ethyl acetate (4×25 ml). The combined organic layers werewashed with water and brine, dried over sodium sulfate and concentrated.The residue was purified by chromatography on silica gel (ethylacetate/cyclohexane 1:1). Yield: 329 mg of1-cyclohexyloxy-4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one(title compound P2ii.26) as a slight tan foam. Trituration with hexanegave a white solid, mp 115-118° C.

¹H-NMR (CD₃OD): 1.20-1.38 (m, 3H), 1.47 (m, 2H), 1.58 (m, 1H), 1.85 (m,4H), 2.06 (m, 2H), 2.11 (s, 6H), 2.25 (s, 3H), 2.39 (m, 2H), 3.12-3.29(m, 2H), 3.30-3.48 (m, 2H), 3.55 (s, 3H), 3.98 (m, 1H), 6.90 (s, 2H).

LC/MS (ES+): 415 (M+H)⁺.

EXAMPLE 19 Preparation of1-Methoxy-4-{(1-methoxy-piperidin-4-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (compound P3ii.26) Step 1: Preparation of1-methoxy-piperidin-4-ol

To a solution of 1-methoxy-piperidin-4-one [prepared according toJournal of Organic Chemistry (1961), 26, 1867-74] (15.0 g, 116.1 mmol)in ethanol (430 ml) was added sodium borohydride 96% (2.29 g, 58.1 mmol)in portions. The reaction mixture was stirred at room temperature for 5hours, evaporated to half of its volume, poured on cold saturatedaqueous ammonium chloride and thoroughly extracted with ethyl acetate.The combined organic layers were washed with brine, dried over sodiumsulfate and concentrated. The residue was purified by chromatography onsilica gel (ethyl acetate). Yield: 10.9 g of 1-methoxy-piperidin-4-ol asa liquid.

¹H-NMR (CDCl₃): 1.46-2.06 (br signals, total 5H), 2.34-3.40 (br signals,total 4H), 3.53 (s, 3H), 3.59-3.96 (br signals, total 1H).

LC/MS (ES+): 132 (M+H)⁺

Step 2: Preparation of1-methoxy-4-{(1-methoxy-piperidin-4-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (title compound P3ii.26)

To a solution of triphenylphosphine (1.11 g, 4.23 mmol) in THF (20 ml)at 0° C. was added diisopropyl azodicarboxylate (0.83 ml, 0.85 g, 4.24mmol) dropwise and the resulting precipitate was stirred at 0° C. for 30minutes.4-{Hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.3 obtained in analogy to preparationexample 11, step 4) (1.3 g, 3.57 mmol) was further added in one portion,followed by a solution of 1-methoxy-piperidin-4-ol (0.53 g, 4.04 mmol)in THF (6 ml) dropwise at 0° C. The reaction mixture was stirred at roomtemperature for two hours and concentrated in vacuo. The residue wastriturated with hexane and filtered to remove part of the insolubletriphenylphosphine oxide. The filtrate was evaporated and the residuepurified by chromatography on silica gel (gradient ethyl acetate/heptane3:7→ethyl acetate). Yield: 861 mg of pure1-methoxy-4-{(1-methoxy-piperidin-4-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylicacid methyl ester (title compound P3ii.26) as a colorless gum, followedby a second fraction of compound P3ii.26 (701 mg) slightly contaminatedwith triphenylphosphine oxide.

¹H-NMR (CD₃OD, selected signals only): 2.19 (s, 6H, mesityl CH₃), 2.23(s, 3H, mesityl CH₃), 3.52 (br s, 3H, NOCH₃), 3.54 (br s, 3H, NOCH₃),3.65 (s, 3H, COOCH₃), 6.82 (s, 2H, mesityl H_(arom)).

LC/MS (ES+): 478 (M+H)⁺

EXAMPLE 20 Preparation of Carbonic acid3-(4-chloro-2,6-dimethyl-phenyl)-1-ethoxycarbonyloxy-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-ylester ethyl ester (compound P1ii.115) Step 1: Preparation of4-{[2-(4-chloro-2,6-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.34)

To a solution of (4-chloro-2,6-dimethyl-phenyl)-acetyl chloride (2.90 g,13.4 mmol) in THF (25 ml) was added sodium hydrogen carbonate (1.90 g,22.7 mmol) at 0° C., followed by4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid methyl ester(preparation example 11, step 3; compound P4ii.2) (2.73 g, 13.4 mmol)dissolved in THF (25 ml) dropwise. The reaction mixture was stirred at0° C. for 30 minutes, then further 30 minutes at room temperature. Aftercompletion of the reaction indicated by TLC and LC/MS, the reactionmixture was filtered and the residue (NaCl) washed with THF. Thefiltrate was concentrated to dryness and stirred several times withlittle amounts of an ether/hexane mixture (1:1) to remove side products.Finally, the compound was washed with ether to yield pure4-{[2-(4-chloro-2,6-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (compound P3ii.34) as white solid. Yield: 3.7 g, mp228-231° C.

¹H-NMR (DMSO-d₆): 1.77-1.91 (br m, 1H), 1.91-2.05 (br m, 1H), 2.13 (s,6H), 2.30-2.42 (br m, 1H), 2.45-2.55 (br m, 1H; covered by DMSO solventpeak), 2.62-2.80 (br m, 2H), 3.05-3.21 (br m, 2H), 3.40 (s, 3H), 3.55(s, 3H), 3.70-3.85 (br m, 2H), 7.05 (s, 2H).

LC/MS (ES+): 385/387 (M+H)⁺

Step 2: Preparation of3-(4-chloro-2,6-dimethyl-phenyl)-1,4-dihydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.103)

To a suspension of4-{[2-(4-chloro-2,6-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylicacid methyl ester (0.40 g, 1.04 mmol) in dimethylformamide (3 ml) at 0°C. was added potassium tert-butoxide (0.35 g, 3.12 mmol) in portions.After completion of the addition, stirring was continued at 0° C. for 30minutes and at room temperature overnight. The reaction mixture waspoured into cold water (0° C.), the pH adjusted to ca 5.5 by adding 1 NHCl and then thoroughly extracted with ethyl acetate (three times). Thecombined organic layers were washed with water and brine, dried oversodium sulfate and concentrated. The resulting crude material waspurified by column chromatography on silica gel (gradient ethylacetate/cyclohexane 1:1→ethyl acetate). Yield: 0.14 g of3-(4-chloro-2,6-dimethyl-phenyl)-1,4-dihydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.103) as a white solid.

¹H-NMR (CD₃OD): 1.95-2.10 (br m, 2H), 2.15-2.30 (br m, 2H), 2.18 (s,6H), 3.20-3.50 (br m, total 4H), 3.55 (s, 3H), 7.14 (s, 2H).

LC/MS (ES+): 353/355 (M+H)⁺

Step 3: Preparation of carbonic acid3-(4-chloro-2,6-dimethyl-phenyl)-1-ethoxycarbonyloxy-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-ylester ethyl ester (title compound P1ii.115)

To a solution of3-(4-chloro-2,6-dimethyl-phenyl)-1,4-dihydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(140 mg, 0.40 mmol) and triethylamine (0.1 ml, 72 mg, 0.71 mmol) in THF(3 ml) at 0° C. was added a solution of ethyl chloroformate (0.05 ml, 52mg, 0.48 mmol) dissolved in THF (2 ml) dropwise. The suspension wasstirred at 0° C. for 30 minutes. Then the reaction mixture was pouredinto cold (0° C.) water and thoroughly extracted three times with ethylacetate. The combined organic layers were washed with water and brine,dried over sodium sulfate and concentrated. The raw material waspurified by column chromatography on silica gel (ethylacetate/cyclohexane 1:4). Yield: 70 mg of carbonic acid3-(4-chloro-2,6-dimethyl-phenyl)-1-ethoxycarbonyloxy-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-ylester ethyl ester (title compound P1ii.115) as a colorless gum.

¹H-NMR (CDCl₃): 1.09 (t, 3H), 1.39 (t, 3H), 2.08-2.30 (br m, 4H), 2.19(s, 6H), 2.70-3.13 (br m, total 2H), 3.20-3.42 (br m, 2H), 3.55 (s, 3H),4.03 (q, 2H), 4.38 (br q, 2H), 7.05 (s, 2H).

LC/MS (ES+): 497/499 (M+H)⁺

EXAMPLE 21 Preparation of Cyclopropanecarboxylic acid3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxymethoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1 ii.4)

To a solution of3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.2) (200 mg, 0.55 mmol), triethylamine (0.153 ml, 111 mg,1.10 mmol) and a catalytic amount of 4-dimethylaminopyridine intetrahydrofuran (6 ml) at 0° C. was added cyclopropanecarboxylic acidchloride (0.066 ml, 75 mg, 0.72 mmol) dropwise. The suspension wasstirred at 0° C. for 10 minutes, and at room temperature for one hour.The reaction mixture was evaporated, diluted with ethyl acetate andfiltered to remove salts. The filtrate was washed with a saturatedaqueous sodium hydrogen carbonate solution and brine, dried over sodiumsulfate and concentrated. The residue was purified by chromatography onsilica gel (ethyl acetate/hexane 1:2) to afford 200 mg of an oilyproduct. This material was triturated with diethyl ether, filtered anddried. Yield: 190 mg of cyclopropanecarboxylic acid3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxymethoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (title compound P1ii.4) as a white solid, mp 114-116° C.

¹H-NMR (CDCl₃): 0.75-0.92 (br m, 4H), 1.63 (br m, 1H), 1.72-2.03 (br m,2H), 2.19 (s, 3H), 2.28 (s, 3H), 2.47 (br m, 2H), 2.88 (br m, 1H),3.16-3.45 (br m, 3H), 3.56 (s, 3H), 3.64 (s, 3H), 5.07 (br s, 2H), 6.91(s, 1H), 7.02 (d, 1H), 7.08 (d, 1H).

LC/MS (ES+): 431 (M+H)⁺

EXAMPLE 22 Preparation of Carbonic acid ethyl ester1-(2-methanesulfinyl-ethoxy)-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1ii.111)

To a solution of carbonic acid ethyl ester8-methoxy-1-(2-methylsulfanyl-ethoxy)-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (compound P1ii.110) (400 mg, 0.84 mmol) in dichloromethane (10 ml)at 0° C. was added 3-chloroperbenzoic acid (210 mg, MCPBA ˜70%, 0.85mmol). The reaction mixture was stirred at room temperature overnight,then poured on saturated aqueous sodium metabisulfite and the layersseparated. The aqueous phase was extracted with dichloromethane (3×),the combined organic layers were washed with water and brine, dried oversodium sulfate and concentrated. The residue was purified bychromatography on silica gel (ethyl acetate/methanol 20:1). Yield: 220mg of carbonic acid ethyl ester1-(2-methanesulfinyl-ethoxy)-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-ylester (title compound P1ii.111) as a colorless gum.

¹H-NMR (CD₃OD): 1.03 (t, 3H), 2.05 (br m, 2H), 2.13 (s, 3H), 2.14 (s,3H), 2.26 (s, 3H), 2.33 (m, 2H), 2.75 (s, 3H), 2.96 (br m, 1H),3.09-3.46 (br m, total 5H), 3.55 (s, 3H), 4.01 (q, 2H), 4.59 (m, 2H),6.89 (s, 2H).

LC/MS (ES+): 495 (M+H)⁺

EXAMPLE 23 Preparation of2-(4-Chloro-2,6-dimethyl-phenyl)-N-(4-cyano-1-methoxy-piperidin-4-yl)-N-ethoxy-acetamide(compound P3ii.49) Step 1: Preparation of 1-methoxy-piperidin-4-oneO-ethyl-oxime

Obtained from 1-methoxy-piperidin-4-one (20 g, 154.85 mmol),triethylamine (47.4 ml, 34.5 g, 340.66 mmol) and O-ethyl-hydroxylaminehydrochloride (30.2 g, 309.69 mmol) in methanol (300 ml) according toprocedure ‘EXAMPLE 11, Step 1’. Yield: 22.02 g of1-methoxy-piperidin-4-one O-ethyl-oxime as a colorless, viscous liquid.This material was used without further purification in the next step.

¹H-NMR (CDCl₃): 1.25 (t, 3H), 2.20-3.40 (br signals, total 8H), 3.55 (s,3H), 4.07 (q, 2H).

LC/MS (ES+): 173 (M+H)⁺

Step 2: Preparation of 4-ethoxyamino-1-methoxy-piperidine-4-carbonitrile(compound P4ii.3)

Obtained from 1-methoxy-piperidin-4-one O-ethyl-oxime (10 g, 58.06mmol), potassium dihydrogen phosphate (31.6 g, 232.20 mmol) in water (50ml) at 0-5° C. to which was added a solution of potassium cyanide (6.81g, 104.58 mmol) in water (50 ml) according to procedure ‘EXAMPLE 11,Step 2’. The reaction mixture was stirred at room temperature for 2 days[treated in between with another portion of potassium dihydrogenphosphate (7.9 g) and potassium cyanide (1.9 g)] and at 40° C. for 4days [again treated in between with another portion of potassiumdihydrogen phosphate (7.9 g) and potassium cyanide (1.9 g)]. The mixturewas flushed with nitrogen, the aqueous layer saturated with sodiumchloride and extracted with diethyl ether (4×150 ml). The combinedorganic layers were washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by chromatography on silica gel(ethyl acetate/cyclohexane 1:2). Yield: 5.1 g of4-ethoxyamino-1-methoxy-piperidine-4-carbonitrile (compound P4ii.3) as apale yellow oil.

¹H-NMR (CDCl₃): 1.19 (t, 3H), 1.59-2.29 (br signals, total 4H),2.64-3.43 (br signals, total 4H), 3.52 (s, 3H), 3.80 (q, 2H), 5.37 (brs, 1H).

IR(CN): ν 2235.3 cm⁻¹. LC/MS (ES+): 200 (M+H)⁺

Step 3: Preparation of2-(4-chloro-2,6-dimethyl-phenyl)-N-(4-cyano-1-methoxy-piperidin-4-yl)-N-ethoxy-acetamide(title compound P3ii.49)

To a solution of 4-ethoxyamino-1-methoxy-piperidine-4-carbonitrile (2.0g, 10.04 mmol), triethylamine (3.49 ml, 2.54 g, 25.09 mmol) and acatalytic amount of 4-dimethylamino-pyridine in tetrahydrofuran (10 ml)at 0° C. was added a solution of (4-chloro-2,6-dimethyl-phenyl)-acetylchloride (2.18 g, 10.04 mmol) in tetrahydrofuran (1 ml) dropwise. Thesuspension was stirred at 0° C. for 15 minutes, and at room temperatureovernight. The reaction mixture was evaporated, diluted with ethylacetate and water, and the layers separated. The aqueous phase wasextracted with ethyl acetate, the combined organic layers washed withbrine, dried over sodium sulfate and concentrated. The crude materialwas triturated with diisopropyl ether, filtered and the filtrateconcentrated. The oily residue was purified by chromatography on silicagel (ethyl acetate/hexane 1:1). Yield: 1.53 g of2-(4-chloro-2,6-dimethyl-phenyl)-N-(4-cyano-1-methoxy-piperidin-4-yl)-N-ethoxy-acetamide(title compound P3ii.49) as a colorless oil, which solidified uponstanding, mp 100-103° C.

¹H-NMR (CDCl₃): 1.36 (t, 3H), 2.00-3.44 (br signals, total 8H), 2.24 (s,6H), 3.51 (br s, 3H), 3.63 (br d, 1H), 4.04 (br d, 1H), 4.13 (br q, 2H),7.04 (s, 2H).

IR(CN): ν 2243.4 cm⁻¹. LC/MS (ES+): 380/382 (M+H)⁺

EXAMPLE 24 Preparation of3-(4′-Chloro-3,5-dimethyl-biphenyl-4-yl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.15)

To a suspension of3-(4-bromo-2,6-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.14) (500 mg, 1.13 mmol) in dimethoxyethane (22 ml) undernitrogen atmosphere was added tetrakis(triphenylphosphine)palladium(0)(65 mg, 0.056 mmol) and the mixture stirred at room temperature for 15minutes. After further addition of water (4.3 ml), 4-chlorophenylboronicacid (213 mg, 1.36 mmol) and sodium carbonate (410 mg, 3.87 mmol), themixture was heated at reflux for 3 hours. The reaction mixture wasacidified at room temperature with 1N hydrochloric acid and extractedwith ethyl acetate (3×). The combined organic layers were washed withbrine, dried over sodium sulfate and concentrated. The residue waspurified by chromatography on silica gel (ethyl acetate/heptane 5:3) toafford 150 mg of an gummy product. This material was triturated withmethanol, filtered and dried. Yield: 90 mg of3-(4′-chloro-3,5-dimethyl-biphenyl-4-yl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one(compound P2ii.15) as a white solid, mp 128° C. (dec).

¹H-NMR (CDCl₃, selected signals only): 2.27 (br s, 6H, mesityl CH₃),3.60 (br s, 3H, OCH₃), 3.62 (br s, 3H, OCH₃), 5.05 (s, 2H, OCH₂OCH₃),7.26 (s, 2H, H_(arom)), 7.39 (d, 2H, H_(arom)), 7.49 (d, 2H, H_(arom)).

LC/MS (ES+): 473/475 (M+H)⁺

EXAMPLE 25 Alternative preparation of4-Hydroxyamino-1-methoxy-piperidine-4-carboxylic acid methyl ester(compound P4ii.2) Step 1: Preparation of4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid (compound P4ii.4)

4-Hydroxyamino-1-methoxy-piperidine-4-carbonitrile (compound P4ii.1)(1.5 g, 8.76 mmol) was added in two portions to concentrated sulfuricacid (15 ml) at 0° C. After stirring for 20 minutes, a yellow solutionwas obtained which was kept at room temperature for two days. Thereaction mixture was diluted with ice water (30 ml), heated at refluxfor 4 hours, then poured on ice (25 g) and neutralised with 25% aqueousammonia under cooling to pH 7-8. The reaction mixture was evaporated andthe white solid residue triturated with warm (40° C.) methanol (3×50ml), filtered and the combined methanol phases concentrated. The residuewas treated with toluene (3×50 ml) to remove water azeotropically untilconstant weight, then triturated with tetrahydrofuran, filtered anddried. Yield: 1.58 g of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylicacid (compound P4ii.4) as a white solid, mp 180° C. (dec).

¹H-NMR (CD₃OD): 1.54-2.29 (br signals, total 4H), 2.82 (br m, 2H),3.07-3.26 (br signals, total 2H), 3.49 (s, 3H).

LC/MS (ES+): 191 (M+H)⁺

Step 2: Preparation of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylicacid methyl ester (title compound P4ii.2)

To a suspension of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid(1.0 g, 5.26 mmol) in methanol (25 ml) at 0-10° C. was added thionylchloride (1.14 ml, 1.88 g, 15.77 mmol) and the reaction mixture washeated at reflux for 48 hours. After cooling, the mixture wasconcentrated, the residue diluted with ice water (20 ml) and neutralisedwith aqueous sodium bicarbonate. The aqueous phase was extracted withdiethyl ether (3×25 ml), the combined organic layers washed with aqueoussodium bicarbonate and brine, dried over sodium sulfate andconcentrated. Yield: 0.53 g of4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid methyl ester(title compound P4ii.2) as a viscous, yellowish oil. This material wasidentical to the compound described above under preparation ‘EXAMPLE 11,Step 3’.

LC/MS (ES+): 205 (M+H)⁺

Compounds of the formula I from Table P1 ii, compounds from Table P2iiand intermediates listed in Tables P3ii and P4ii can be prepared byanalogous procedures. Either one of the following LC-MS methods was usedto characterize the compounds:

Method A

MS:

ZQ Mass Spectrometer from Waters (Single quadrupole mass spectrometer);Ionisation method: Electrospray; Polarity: positive/negative ions;Capillary (kV) 3.00, Cone (V) 30.00, Extractor (V) 2.00, SourceTemperature (° C.) 100, Desolvation Temperature (° C.) 250, Cone GasFlow (L/Hr) 50, Desolvation Gas Flow (L/Hr) 400; Mass range: 150 to 1000or 100 to 900 Da.

LC:

HP 1100 HPLC from Agilent: solvent degasser, quaternary pump(ZCQ)/binary pump (ZDQ), heated column compartment and diode-arraydetector. Column: Phenomenex Gemini C18, 3 μm particle size, 110Angstrom, 30×3 mm, Temp: 60° C.; DAD Wavelength range (nm): 200 to 500;Solvent gradient: A=water+0.05% v/v HCOOH, B=Acetonitril/Methanol (4:1,v/v)+0.04% v/v HCOOH.

Time (min) A % B % Flow (ml/min) 0.00 95.0 5.0 1.700 2.00 0.0 100.01.700 2.80 0.0 100.0 1.700 2.90 95.0 5.0 1.700 3.00 95.0 5.0 1.700

Method B

MS:

ZMD Mass Spectrometer from Waters (Single quadrupole mass spectrometer);Ionisation method: Electrospray; Polarity: positive/negative ions;Capillary (kV) 3.80, Cone (V) 30.00, Extractor (V) 3.00, SourceTemperature (° C.) 150, Desolvation Temperature (° C.) 350, Cone GasFlow (L/Hr) OFF, Desolvation Gas Flow (L/Hr) 600; Mass range: 150 to1000 (100 to 1500 for LowMass) or 100 to 900 Da.

LC:

HP 1100 HPLC from Agilent: solvent degasser, binary pump, heated columncompartment and diode-array detector. Column: Phenomenex Gemini C18, 3μm particle size, 110 Angstrom, 30×3 mm, Temp: 60° C.; DAD Wavelengthrange (nm): 200 to 500; Solvent gradient: A=water+0.05% v/v HCOOH,B=Acetonitril/Methanol (4:1, v:v)+0.04% v/v HCOOH.

Time (min) A % B % Flow (ml/min) 0.00 95.0 5.0 1.700 2.00 0.0 100.01.700 2.80 0.0 100.0 1.700 2.90 95.0 5.0 1.700 3.00 95.0 5.0 1.700

The characteristic values obtained for each compound were the retentiontime (“R_(t)”, recorded in minutes) and the molecular ion as listed inTable P1ii, Table P2ii, Table P3ii and in Table P4ii.

TABLE P1ii Physical data of compounds of formula I: Compound No.Structures Melting Point MS/NMR P1ii.1

gum LC/MS: 405 (M + H)⁺ R_(t) = 1.88 min P1ii.2

  EXAMPLE 11, step 6 109-111° C. LC/MS: 435 (M + H)⁺ R_(t) = 1.90 minP1ii.3

gum LC/MS: 449 (M + H)⁺ R_(t) = 1.91 min P1ii.4

  EXAMPLE 21 114-116° C. LC/MS: 431 (M + H)⁺ R_(t) = 1.87 min P1ii.5

 93-95° C. LC/MS: 461 (M + H)⁺ R_(t) = 2.12 min P1ii.6

gum LC/MS: 463 (M + H)⁺ R_(t) = 1.95 min P1ii.7

109-111° C. LC/MS: 449 (M + H)⁺ R_(t) = 1.95 min P1ii.8

 96-97° C. LC/MS: 419 (M + H)⁺ R_(t) = 1.91 min P1ii.9

  EXAMPLE 13, step 2 100-102° C. LC/MS: 475 (M + H)⁺ R_(t) = 1.97 minP1ii.10

130-132° C. LC/MS: 489 (M + H)⁺ R_(t) = 2.05 min P1ii.11

  EXAMPLE 13, step 1 154-155° C. LC/MS: 405 (M + H)⁺ R_(t) = 1.79 minP1ii.12

 78-81° C. LC/MS: 391 (M + H)⁺ R_(t) = 1.67 min P1ii.13

  EXAMPLE 15 gum LC/MS: 463 (M + H)⁺ R_(t) = 1.98 min P1ii.14

gum LC/MS: 447 (M + H)⁺ R_(t) = 2.07 min P1ii.15

 84-86° C. LC/MS: 433 (M + H)⁺ R_(t) = 1.98 min P1ii.16

gum LC/MS: 473 (M + H)⁺ R_(t) = 2.03 min P1ii.17

gum LC/MS: 445 (M + H)⁺ R_(t) = 2.04 min P1ii.18

gum LC/MS: 459 (M + H)⁺ R_(t) = 2.09 min P1ii.19

 83-85° C. LC/MS: 513/515 (M + H)⁺ R_(t) = 2.03 min P1ii.20

110-113° C. LC/MS: 545/547 (M + H)⁺ R_(t) = 2.20 min P1ii.21

118-121° C. LC/MS: 499/501 (M + H)⁺ R_(t) = 1.96 min P1ii.22

gum LC/MS: 531/533 (M + H)⁺ R_(t) = 2.15 min P1ii.23

132-134° C. LC/MS: 489 (M + H)⁺ R_(t) = 1.99 min P1ii.24

 53-55° C. LC/MS: 489 (M + H)⁺ R_(t) = 2.04 min P1ii.25

gum LC/MS: 533 (M + H)⁺ R_(t) = 2.12 min P1ii.26

 74-76° C. LC/MS: 503 (M + H)⁺ R_(t) = 2.10 min P1ii.27

 57-59° C. LC/MS: 493 (M + H)⁺ R_(t) = 1.96 min P1ii.28

gum LC/MS: 473 (M + H)⁺ R_(t) = 2.17 min P1ii.29

gum LC/MS: 443 (M + H)⁺ R_(t) = 1.99 min P1ii.30

gum LC/MS: 487 (M + H)⁺ R_(t) = 2.19 min P1ii.31

 91-93° C. LC/MS: 377 (M + H)⁺ R_(t) = 1.79 min P1ii.32

gum LC/MS: 469/471 (M + H)⁺ R_(t) = 1.94 min P1ii.33

gum LC/MS: 483/485 (M + H)⁺ R_(t) = 1.93 min P1ii.34

gum LC/MS: 439/441 (M + H)⁺ R_(t) = 1.91 min P1ii.35

solid LC/MS: 483/485 (M + H)⁺ R_(t) = 1.87 min P1ii.36

gum LC/MS: 463 (M + H)⁺ R_(t) = 1.91 min P1ii.37

gum LC/MS: 439/441 (M + H)⁺ R_(t) = 1.91 min P1ii.38

solid LC/MS: 469/471 (M + H)⁺ R_(t) = 1.90 min P1ii.39

gum LC/MS: 439/441 (M + H)⁺ R_(t) = 1.84 min P1ii.40

gum LC/MS: 487/489 (M + H)⁺ R_(t) = 1.84 min P1ii.41

solid LC/MS: 443/445 (M + H)⁺ R_(t) = 1.82 min P1ii.42

119-123° C. LC/MS: 473/475 (M + H)⁺ R_(t) = 1.85 min P1ii.43

135-137° C. LC/MS: 499/501 (M + H)⁺ R_(t) = 1.89 min P1ii.44

122-125° C. LC/MS: 477 (M + H)⁺ R_(t) = 1.97 min P1ii.45

gum LC/MS: 459 (M + H)⁺ R_(t) = 2.07 min P1ii.46

gum LC/MS: 477 (M + H)⁺ R_(t) = 1.95 min P1ii.47

gum LC/MS: 461 (M + H)⁺ R_(t) = 1.92 min P1ii.48

gum LC/MS: 405 (M + H)⁺ R_(t) = 1.83 min P1ii.49

powder LC/MS: 449 (M + H)⁺ R_(t) = 1.95 min P1ii.50

128-130° C. LC/MS: 435 (M + H)⁺ R_(t) = 1.87 min P1ii.51

gum ¹H-NMR (CDCl₃): 1.17 (t, 3H), 2.02-2.31 (br m, total 4H), 2.20 (s,3H), 2.22 (s, 3H), 2.91-3.47 (br m, total 4H), 3.43 (s, 3H), 3.56 (s,3H), 3.72 (br m, 2H), 4.08 (q, 2H), 4.35 (br m, 2H), 7.06 (s, 1H), 7.35(s, 1H). P1ii.52

gum LC/MS: 513/515 (M + H)⁺ R_(t) = 1.92 min P1ii.53

gum LC/MS: 449 (M + H)⁺ R_(t) = 1.90 min P1ii.54

gum LC/MS: 475 (M + H)⁺ R_(t) = 1.96 min P1ii.55

gum LC/MS: 469/471 (M + H)⁺ R_(t) = 1.96 min P1ii.56

gum LC/MS: 449 (M + H)⁺ R_(t) = 1.88 min P1ii.57

gum LC/MS: 419 (M + H)⁺ R_(t) = 1.90 min P1ii.58

gum LC/MS: 487/489 (M + H)⁺ R_(t) = 1.84 min P1ii.59

gum LC/MS: 469/471 (M + H)⁺ R_(t) = 1.87 min P1ii.60

gum LC/MS: 483/485 (M + H)⁺ R_(t) = 1.86 min P1ii.61

116-119° C. LC/MS: 473/475 (M + H)⁺ R_(t) = 1.80 min P1ii.62

gum LC/MS: 513/515 (M + H)⁺ R_(t) = 2.01 min P1ii.63

gum LC/MS: 539/541 (M + H)⁺ R_(t) = 2.01 min P1ii.64

gum LC/MS: 495/497 (M + H)⁺ R_(t) = 1.95 min P1ii.65

gum LC/MS: 483/485 (M + H)⁺ R_(t) = 1.94 min P1ii.66

 90-94° C. LC/MS: 483/485 (M + H)⁺ R_(t) = 1.89 min P1ii.67

gum LC/MS: 527/529 (M + H)⁺ R_(t) = 1.92 min P1ii.68

gum LC/MS: 513/515 (M + H)⁺ R_(t) = 1.91 min P1ii.69

gum LC/MS: 539/541 (M + H)⁺ R_(t) = 1.97 min P1ii.70

gum LC/MS: 439/441 (M + H)⁺ R_(t) = 1.88 min P1ii.71

gum LC/MS: 443/445 (M + H)⁺ R_(t) = 1.79 min P1ii.72

gum LC/MS: 527/529 (M + H)⁺ R_(t) = 1.97 min P1ii.73

gum LC/MS: 449 (M + H)⁺ R_(t) = 1.84 min P1ii.74

gum LC/MS: 405 (M + H)⁺ R_(t) = 1.81 min P1ii.75

gum LC/MS: 543/545 (M + H)⁺ R_(t) = 1.97 min P1ii.76

gum LC/MS: 489 (M + H)⁺ R_(t) = 1.93 min P1ii.77

gum LC/MS: 485 (M + H)⁺ R_(t) = 2.02 min P1ii.78

gum LC/MS: 489 (M + H)⁺ R_(t) = 1.95 min P1ii.79

gum LC/MS: 461 (M + H)⁺ R_(t) = 1.87 min P1ii.80

gum LC/MS: 519 (M + H)⁺ R_(t) = 2.14 min P1ii.81

gum LC/MS: 485 (M + H)⁺ R_(t) = 2.03 min P1ii.82

gum LC/MS: 503 (M + H)⁺ R_(t) = 1.98 min P1ii.83

gum LC/MS: 487 (M + H)⁺ R_(t) = 2.23 min P1ii.84

105-107° C. LC/MS: 503 (M + H)⁺ R_(t) = 2.03 min P1ii.85

gum LC/MS: 539/541 (M + H)⁺ R_(t) = 2.03 min P1ii.86

gum LC/MS: 483/485 (M + H)⁺ R_(t) = 1.94 min P1ii.87

gum LC/MS: 513/515 (M + H)⁺ R_(t) = 1.95 min P1ii.88

113-116° C. LC/MS: 483/485 (M + H)⁺ R_(t) = 1.96 min P1ii.89

gum LC/MS: 527/529 (M + H)⁺ R_(t) = 1.98 min P1ii.90

gum LC/MS: 475 (M + H)⁺ R_(t) = 2.05 min P1ii.91

gum LC/MS: 463 (M + H)⁺ R_(t) = 1.89 min P1ii.92

solid LC/MS: 461 (M + H)⁺ R_(t) = 1.95 min P1ii.93

gum LC/MS: 497/499 (M + H)⁺ R_(t) = 1.97 min P1ii.94

gum LC/MS: 487 (M + H)⁺ R_(t) = 2.12 min P1ii.95

gum LC/MS: 475 (M + H)⁺ R_(t) = 1.95 min P1ii.96

gum LC/MS: 473 (M + H)⁺ R_(t) = 2.00 min P1ii.97

gum LC/MS: 509/511 (M + H)⁺ R_(t) = 2.02 min P1ii.98

gum LC/MS: 531/533 (M + H)⁺ R_(t) = 1.92 min P1ii.99

gum LC/MS: 487/489 (M + H)⁺ R_(t) = 1.93 min P1ii.100

gum LC/MS: 517/519 (M + H)⁺ R_(t) = 1.94 min P1ii.101

gum LC/MS: 425/427 (M + H)⁺ R_(t) = 1.83 min P1ii.102

134-138° C. LC/MS: 499/501 (M + H)⁺ R_(t) = 1.90 min P1ii.103

gum LC/MS: 495/497 (M + H)⁺ R_(t) = 2.03 min P1ii.104

gum LC/MS: 518 (M + H)⁺ R_(t) = 1.97 min P1ii.105

gum LC/MS: 501 (M + H)⁺ R_(t) = 2.26 min P1ii.106

gum LC/MS: 473 (M + H)⁺ R_(t) = 2.15 min P1ii.107

gum LC/MS: 495/497 (M + H)⁺ R_(t) = 1.95 min P1ii.108

gum LC/MS: 475 (M + H)⁺ R_(t) = 1.94 min P1ii.109

gum LC/MS: 503 (M + H)⁺ R_(t) = 2.04 min P1ii.110

gum LC/MS: 479 (M + H)⁺ R_(t) = 2.03 min P1ii.111

  EXAMPLE 22 gum LC/MS: 495 (M + H)⁺ R_(t) = 1.74 min P1ii.112

P1ii.113

gum LC/MS: 483/485 (M + H)⁺ R_(t) = 1.94 min P1ii.114

122-125° C. LC/MS: 439/441 (M + H)⁺ R_(t) = 1.92 min P1ii.115

  EXAMPLE 20, step 3 gum LC/MS: 497/499 (M + H)⁺ R_(t) = 2.02 minP1ii.116

gum LC/MS: 469/471 (M + H)⁺ R_(t) = 1.97 min P1ii.117

gum LC/MS: 495/497 (M + H)⁺ R_(t) = 2.02 min

TABLE P2ii Physical data of compounds of formula II Compound No.Structures Melting Point MS/NMR P2ii.1

gum LC/MS: 333 (M + H)⁺ R_(t) = 1.54 min P2ii.2

136-138° C. LC/MS: 363 (M + H)⁺ R_(t) = 1.55 min P2ii.3

gum LC/MS: 377 (M + H)⁺ R_(t) = 1.58 min P2ii.4

152-154° C. LC/MS: 333 (M + H)⁺ R_(t) = 1.40 min P2ii.5

139-142° C. LC/MS: 391 (M + H)⁺ R_(t) = 1.61 min P2ii.6

163-165° C. LC/MS: 377 (M + H)⁺ R_(t) = 1.64 min P2ii.7

70° C. (dec) LC/MS: 347 (M + H)⁺ R_(t) = 1.60 min P2ii.8

167-169° C. LC/MS: 371 (M + H)⁺ R_(t) = 1.66 min P2ii.9

168-170° C. LC/MS: 361 (M + H)⁺ R_(t) = 1.67 min P2ii.10

gum LC/MS: 391 (M + H)⁺ R_(t) = 1.71 min P2ii.11

153-156° C. LC/MS: 375 (M + H)⁺ R_(t) = 1.78 min P2ii.12

162-164° C. LC/MS: 373 (M + H)⁺ R_(t) = 1.73 min P2ii.13

150-153° C. LC/MS: 387 (M + H)⁺ R_(t) = 1.81 min P2ii.14

190-191° C. LC/MS: 441/443 (M + H)⁺ R_(t) = 1.62 min P2ii.15

128° C. (dec) LC/MS: 473/475 (M + H)⁺ R_(t) = 1.97 min P2ii.16

gum LC/MS: 427/429 (M + H)⁺ R_(t) = 1.63 min P2ii.17

68-71° C. LC/MS: 459/461 (M + H)⁺ R_(t) = 1.93 min P2ii.18

144-146° C. LC/MS: 403 (M + H)⁺ R_(t) = 1.66 min P2ii.19

108-111° C. LC/MS: 417 (M + H)⁺ R_(t) = 1.68 min P2ii.20

gum LC/MS: 417 (M + H)⁺ R_(t) = 1.72 min P2ii.21

124-126° C. LC/MS: 417 (M + H)⁺ R_(t) = 1.62 min P2ii.22

135-137° C. LC/MS: 461 (M + H)⁺ R_(t) = 1.87 min P2ii.23

90-93° C. LC/MS: 431 (M + H)⁺ R_(t) = 1.81 min P2ii.24

 98-100° C. LC/MS: 421 (M + H)⁺ R_(t) = 1.62 min P2ii.25

144-147° C. LC/MS: 401 (M + H)⁺ R_(t) = 1.92 min P2ii.26

115-118° C. LC/MS: 415 (M + H)⁺ R_(t) = 1.98 min P2ii.27

139-143° C. LC/MS: 397/399 (M + H)⁺ R_(t) = 1.67 min P2ii.28

128-130° C. LC/MS: 405 (M + H)⁺ R_(t) = 1.69 min P2ii.29

49-54° C. LC/MS: 411/413 (M + H)⁺ R_(t) = 1.68 min P2ii.30

gum LC/MS: 387 (M + H)⁺ R_(t) = 1.82 min P2ii.31

92-95° C. LC/MS: 367/369 (M + H)⁺ R_(t) = 1.64 min P2ii.32

solid LC/MS: 411/413 (M + H)⁺ R_(t) = 1.66 min P2ii.33

solid LC/MS: 389 (M + H)⁺ R_(t) = 1.63 min P2ii.34

79-82° C. LC/MS: 397/399 (M + H)⁺ R_(t) = 1.55 min P2ii.35

161-163° C. LC/MS: 411/413 (M + H)⁺ R_(t) = 1.55 min P2ii.36

gum LC/MS: 347 (M + H)⁺ R_(t) = 1.59 min P2ii.37

gum LC/MS: 391 (M + H)⁺ R_(t) = 1.65 min P2ii.38

gum LC/MS: 377 (M + H)⁺ R_(t) = 1.60 min P2ii.39

gum LC/MS: 403 (M + H)⁺ R_(t) = 1.72 min P2ii.40

gum LC/MS: 367/369 (M + H)⁺ R_(t) = 1.58 min P2ii.41

solid LC/MS: 441/443 (M + H)⁺ R_(t) = 1.64 min P2ii.42

solid LC/MS: 395/397 (M − H)⁻ R_(t) = 1.64 min P2ii.43

solid LC/MS: 367/369 (M + H)⁺ R_(t) = 1.64 min P2ii.44

gum ¹H-NMR (CD₃OD, selected signals only): 1.29 (t, 9H, N(CH₂CH₃)₃),2.23 (d, ⁴J(H,F) = 1.9 Hz, 3H, mesityl CH₃), 3.17 (q, 6H, N(CH₂CH₃)₃),3.54 (s, 3H, NOCH₃) 5.62 (br m, 1H, tetrahydrofuranyl CH). P2ii.45

solid LC/MS: 427/429 (M + H)⁺ R_(t) = 1.62 min P2ii.46

solid LC/MS: 401/403 (M + H)⁺ R_(t) = 1.54 min P2ii.47

gum LC/MS: 415/417 (M + H)⁺ R_(t) = 1.57 min P2ii.48

solid LC/MS: 371/373 (M + H)⁺ R_(t) = 1.55 min P2ii.49

gum LC/MS: 361 (M + H)⁺ R_(t) = 1.63 min P2ii.50

gum ¹H-NMR (CD₃OD, selected signals only): 1.29 (t, 9H, N(CH₂CH₃)₃),2.22 (d, ⁴J(H,F) = 2.2 Hz, 3H, mesityl CH₃), 3.17 (q, 6H, N(CH₂CH₃)₃),3.39 (s, 3H, CH₂CH₂OCH₃), 3.54 (s, 3H, NOCH₃). P2ii.51

powder LC/MS: 333 (M + H)⁺ R_(t) = 1.53 min P2ii.52

133-136° C. P2ii.53

solid LC/MS: 455/457 (M + H)⁺ R_(t) = 1.67 min P2ii.54

gum LC/MS: 377 (M + H)⁺ R_(t) = 1.57 min P2ii.55

176-180° C. LC/MS: 367/369 (M + H)⁺ R_(t) = 1.55 min P2ii.56

185-190° C. LC/MS: 411/413 (M + H)⁺ R_(t) = 1.56 min P2ii.57

148-153° C. LC/MS: 455/457 (M + H)⁺ R_(t) = 1.60 min P2ii.58

83-86° C. LC/MS: 371/373 (M + H)⁺ R_(t) = 1.52 min P2ii.59

55-57° C. LC/MS: 415/417 (M + H)⁺ R_(t) = 1.53 min P2ii.60

155-158° C. LC/MS: 401/403 (M + H)⁺ R_(t) = 1.51 min P2ii.61

powder LC/MS: 377 (M + H)⁺ R_(t) = 1.66 min P2ii.62

91-92° C. LC/MS: 467/469 (M + H)⁺ R_(t) = 1.71 min P2ii.63

84-85° C. LC/MS: 423/425 (M + H)⁺ R_(t) = 1.71 min P2ii.64

154-157° C. LC/MS: 413 (M + H)⁺ R_(t) = 1.77 min P2ii.65

103-106° C. LC/MS: 417 (M + H)⁺ R_(t) = 1.77 min P2ii.66

88-91° C. LC/MS: 389 (M + H)⁺ R_(t) = 1.54 min P2ii.67

69-72° C. LC/MS: 417 (M + H)⁺ R_(t) = 1.64 min P2ii.68

gum LC/MS: 405 (M + H)⁺ R_(t) = 1.65 min P2ii.69

gum LC/MS: 467/469 (M + H)⁺ R_(t) = 1.66 min P2ii.70

gum LC/MS: 411/413 (M + H)⁺ R_(t) = 1.61 min P2ii.71

gum LC/MS: 397/399 (M + H)⁺ R_(t) = 1.60 min P2ii.72

167-171° C. LC/MS: 441/443 (M + H)⁺ R_(t) = 1.58 min P2ii.73

63-64° C. LC/MS: 455/457 (M + H)⁺ R_(t) = 1.72 min P2ii.74

79-80° C. LC/MS: 441/443 (M + H)⁺ R_(t) = 1.70 min P2ii.75

86-87° C. LC/MS: 411/413 (M + H)⁺ R_(t) = 1.69 min P2ii.76

96-97° C. LC/MS: 467/469 (M + H)⁺ R_(t) = 1.78 min P2ii.77

141-144° C. LC/MS: 377 (M + H)⁺ R_(t) = 1.49 min P2ii.78

153-155° C. LC/MS: 333 (M + H)⁺ R_(t) = 1.44 min P2ii.79

188-191° C. LC/MS: 411/413 (M + H)⁺ R_(t) = 1.63 min P2ii.80

163-167° C. LC/MS: 455/457 (M + H)⁺ R_(t) = 1.67 min P2ii.81

gum LC/MS: 471/473 (M + H)⁺ R_(t) = 1.70 min P2ii.82

95-98° C. LC/MS: 447 (M + H)⁺ R_(t) = 1.89 min P2ii.83

155-157° C. LC/MS: 413 (M + H)⁺ R_(t) = 1.75 min P2ii.84

100-103° C. LC/MS: 431 (M + H)⁺ R_(t) = 1.70 min P2ii.85

74-77° C. LC/MS: 415 (M + H)⁺ R_(t) = 1.98 min P2ii.86

88-91° C. LC/MS: 431 (M + H)⁺ R_(t) = 1.62 min P2ii.87

71-74° C. LC/MS: 459/461 (M + H)⁺ R_(t) = 1.66 min P2ii.88

solid LC/MS: 415/417 (M + H)⁺ R_(t) = 1.63 min P2ii.89

64-67° C. LC/MS: 445/447 (M + H)⁺ R_(t) = 1.65 min P2ii.90

solid LC/MS: 391 (M + H)⁺ R_(t) = 1.62 min P2ii.91

foam LC/MS: 403 (M + H)⁺ R_(t) = 1.68 min P2ii.92

86-89° C. LC/MS: 427/429 (M + H)⁺ R_(t) = 1.61 min P2ii.93

88-91° C. LC/MS: 423/425 (M + H)⁺ R_(t) = 1.74 min P2ii.94

84-88° C. LC/MS: 423/425 (M + H)⁺ R_(t) = 1.63 min P2ii.95

solid LC/MS: 446 (M + H)⁺ R_(t) = 1.62 min P2ii.96

169-172° C. LC/MS: 429 (M + H)⁺ R_(t) = 2.05 min P2ii.97

113-115° C. LC/MS: 401 (M + H)⁺ R_(t) = 1.89 min P2ii.98

135-138° C. LC/MS: 403 (M + H)⁺ R_(t) = 1.57 min P2ii.99

113-115° C. LC/MS: 407 (M + H)⁺ R_(t) = 1.72 min P2ii.100

 98-101° C. LC/MS: 431 (M + H)⁺ R_(t) = 1.72 min P2ii.101

161-164° C. LC/MS: 411/413 (M + H)⁺ R_(t) = 1.63 min P2ii.102

88-92° C. LC/MS: 367/369 (M + H)⁺ R_(t) = 1.58 min P2ii.103

solid LC/MS: 353/355 (M + H)⁺ R_(t) = 1.37 min P2ii.104

176-178° C. LC/MS: 397/399 (M + H)⁺ R_(t) = 1.64 min P2ii.105

137-139° C. LC/MS: 421/423 (M − H)⁻ R_(t) = 1.69 min

Intermediates from Table P3ii can be prepared by analogous procedures.

TABLE P3ii Physical data of intermediates Compound No. StructuresMelting Point MS/NMR P3ii.1

  EXAMPLE 11, step 4 EXAMPLE 16, step 2 140-142° C. LC/MS: 351 (M + H)⁺R_(t) = 1.59 min P3ii.2

  EXAMPLE 16, step 1 153-156° C. LC/MS: 318 (M + H)⁺ R_(t) = 1.66 minP3ii.3

199-200° C. LC/MS: 365 (M + H)⁺ R_(t) = 1.68 min P3ii.4

  EXAMPLE 12, step 1 108-110° C. LC/MS: 403 (M + H)⁺ R_(t) = 1.98 minP3ii.5

gum LC/MS: 436 (M + H)⁺ R_(t) = 1.91 min P3ii.6

  EXAMPLE 17, step 1 107-109° C. LC/MS: 435 (M + H)⁺ R_(t) = 2.03 minP3ii.7

gum LC/MS: 433 (M + H)⁺ R_(t) = 2.19 min P3ii.8

  EXAMPLE 18, step 1 gum LC/MS: 447 (M + H)⁺ R_(t) = 2.23 min P3ii.9

gum LC/MS: 379 (M + H)⁺ R_(t) = 1.89 min P3ii.10

gum LC/MS: 449 (M + H)⁺ R_(t) = 1.89 min P3ii.11

 55-57° C. LC/MS: 437 (M + H)⁺ R_(t) = 1.95 min P3ii.12

gum LC/MS: 419 (M + H)⁺ R_(t) = 2.09 min P3ii.13

gum LC/MS: 437 (M + H)⁺ R_(t) = 1.86 min P3ii.14

solid LC/MS: 351 (M + H)⁺ R_(t) = 1.59 min P3ii.15

166-167° C. LC/MS: 429/431 (M + H)⁺ R_(t) = 1.71 min P3ii.16

gum LC/MS: 449 (M + H)⁺ R_(t) = 2.08 min P3ii.17

gum LC/MS: 421 (M + H)⁺ R_(t) = 1.80 min P3ii.18

gum LC/MS: 449 (M + H)⁺ R_(t) = 1.88 min P3ii.19

gum LC/MS: 447 (M + H)⁺ R_(t) = 2.25 min P3ii.20

gum LC/MS: 463 (M + H)⁺ R_(t) = 1.93 min P3ii.21

gum LC/MS: 445 (M + H)⁺ R_(t) = 2.05 min P3ii.22

gum LC/MS: 445 (M + H)⁺ R_(t) = 1.98 min P3ii.23

gum LC/MS: 447 (M + H)⁺ R_(t) = 2.03 min P3ii.24

gum LC/MS: 479 (M + H)⁺ R_(t) = 2.10 min P3ii.25

gum LC/MS: 463 (M + H)⁺ R_(t) = 1.94 min P3ii.26

  EXAMPLE 19, step 2 gum LC/MS: 478 (M + H)⁺ R_(t) = 1.97 min P3ii.27

gum LC/MS: 461 (M + H)⁺ R_(t) = 2.31 min P3ii.28

gum LC/MS: 433 (M + H)⁺ R_(t) = 2.17 min P3ii.29

115-117° C. LC/MS: 435 (M + H)⁺ R_(t) = 1.85 min P3ii.30

gum LC/MS: 463 (M + H)⁺ R_(t) = 2.01 min P3ii.31

gum LC/MS: 439 (M + H)⁺ R_(t) = 2.03 min P3ii.32

solid LC/MS: 429/431 (M + H)⁺ R_(t) = 1.73 min P3ii.33

solid LC/MS: 415/417 (M + H)⁺ R_(t) = 1.67 min P3ii.34

  EXAMPLE 20, step 1 228-231° C. LC/MS: 385/387 (M + H)⁺ R_(t) = 1.71min P3ii.35

LC/MS: 385/387 (M + H)⁺ R_(t) = 1.86 min P3ii.36

LC/MS: 389/391 (M + H)⁺ R_(t) = 1.59 min P3ii.37

LC/MS: 379 (M + H)⁺ R_(t) = 1.91 min P3ii.38

162-163° C. LC/MS: 429/431 (M + H)⁺ R_(t) = 1.76 min P3ii.39

LC/MS: 385/387 (M + H)⁺ R_(t) = 1.67 min P3ii.40

LC/MS: 433/435 (M + H)⁺ R_(t) = 1.69 min P3ii.41

LC/MS: 385/387 (M + H)⁺ R_(t) = 1.69 min P3ii.42

LC/MS: 365 (M + H)⁺ R_(t) = 1.67 min P3ii.43

LC/MS: 351 (M + H)⁺ R_(t) = 1.55 min P3ii.44

LC/MS: 389/391 (M + H)⁺ R_(t) = 1.62 min P3ii.45

LC/MS: 365 (M + H)⁺ R_(t) = 1.66 min P3ii.46

LC/MS: 429/431 (M + H)⁺ R_(t) = 1.67 min P3ii.47

LC/MS: 385/387 (M + H)⁺ R_(t) = 1.71 min P3ii.48

LC/MS: 365 (M + H)⁺ R_(t) = 1.65 min P3ii.49

  EXAMPLE 23, step 3 100-103° C. LC/MS: 380/382 (M + H)⁺ R_(t) = 1.99min

Intermediates from Table P4ii can be prepared by analogous procedures.

TABLE P4ii Physical data of intermediates Compound No. StructuresMelting Point MS/NMR P4ii.1

  EXAMPLE 11, step 2 130-131° C. ¹H-NMR (CDCl₃): 1.55-2.35 (br signals,total 4H), 2.60-3.45 (br signals, total 4H), 3.52 (s, 3H), 5.19 (br s,1H), 5.42 (br s, 1H). IR (CN): v 2227.8 cm⁻¹. LC/MS (ES+): 172 (M + H)⁺;R_(t) = 0.31 min. P4ii.2

  EXAMPLE 11, step 3 Oil ¹H-NMR (CDCl₃): 1.50-2.40 (br signals, total4H), 2.76 (br m, 2H), 3.01- 3.32 (br m, 2H), 3.52 (s, 3H), 3.76 (s, 3H),5.58 (br s, 2H) IR (COOMe): v 1731.3 cm⁻¹. LC/MS (ES+): 205 (M + H)⁺;R_(t) = 0.31 min. P4ii.3

  EXAMPLE 23, step 2 Oil ¹H-NMR (CDCl₃): 1.19 (t, 3H), 1.59-2.29 (brsignals, total 4H), 2.64-3.43 (br signals, total 4H), 3.52 (s, 3H), 3.80(q, 2H), 5.37 (br s, 1H). IR (CN): v 2235.3 cm⁻¹. LC/MS (ES+): 200 (M +H)⁺; R_(t) = 1.21 min. P4ii.4

  example 25, step 1    180° C. ¹H-NMR (CD₃OD): 1.54-2.29 (br signals,total 4H), 2.82 (br m, 2H), 3.07- 3.26 (br signals, total 2H), 3.49 (s,3H). LC/MS (ES+): 191 (M + H)⁺; R_(t) = 0.22 min.

Examples of compounds of formula I where Q is iii are disclosed inWO2009/049851.

BIOLOGICAL EXAMPLES Example B1 Activity Against Rhopalosiphum padi(Cereal Aphid) and Crop Safety

The experiment was divided into two parts, one half of the plants wasused for the aphid bioassay the other half was not infested with aphidsand kept for plant growth evaluation. One replicate consisted of 4 wheatplants per pot. 5 replicates were infested with a mixed population ofcereal aphids 6 days after seeding. 9 days after seeding all wheatplants (10 replicates) were sprayed with respective test solutions. Testsolutions contained the formulated test compound (25 ppm), the adjuvantMero (0.1% v/v), and the plant growth regulator (PGR) CCC(chlormequat-chloride, Cyclocel®) or trinexapac ethyl (Moddus®). 6 and17d after application aphid mortality and phytotoxicity were evaluated.Efficacy was calculated with the aid of Abbott's formula. Assessment onphytotoxicity was done by counting the number of leaves bent down due tonecrosis per pot. Additionally the average plant height per replicatewas measured.

TABLE B1-1 Efficacy (% mortality) against cereal aphids(Rhopalosiphum padi) Ratio Al:PGR PGR 6 DAA 17 DAA Cpd. P1.2, / 97 70Table P1 1:20 Cycocel 97 93 1:10 Moddus 94 90 Cpd. P1.29, / 96 86 TableP1 1:20 Cycocel 94 96 1:10 Moddus 93 87

Tank mixing of PGRs with these insecticides does not adversely affectthe aphid control of test compounds.

TABLE B1-2 Phytotoxicity on wheat no. of leaves bent down mean Ratio(necrotic) plant height (cm) Al:PGR PGR 6 DAA 6 DAA 21 DAA Check / / 024.2 36.0 Check 1:20 Cycocel 0 22.4 29.0 Check 1:10 Moddus 0 22.4 30.0Cpd. P1.2, / 3.8 14.8 36.2 Table P1 1:20 Cycocel 0 19.8 30.2 1:10 Moddus0 18.6 29.2 Cpd. P1.29, / 1.3 19.8 37.0 Table P1 1:20 Cycocel 1 21.429.8 1:10 Moddus 0 21.4 29.8

Tank mixing of PGRs with these insecticides clearly reduced thephytotoxicity of the test compounds. Test compounds caused 6DAA a morepronounced stunting effect on stem height than the commonly used PGRsfor this effect. 21 DAA the plant growth is determined by the appliedPGR.

Example B2

Activity against Nilaparvata lugens (brown plant hopper, BPH) and cropsafety The experiment was divided into two parts, one half of the plantswas used for the plant hoppers bioassay the other half was not infestedwith insects and kept for plant growth evaluation. Eight replicates(pots with rice plants) were sprayed with respective test solutions.Test solutions contained the formulated test compound and the PGRModdus® at different ratios. 4 pots were infested with plant hoppernymphs right after application. 7d after application BPH mortality andphytotoxicity were evaluated. Efficacy was calculated with the aid ofAbbott's formula. Assessment on phytotoxicity was done by counting thenumber of leaves with chlorosis per pot.

TABLE B2-1 Efficacy (% mortality) against brown plant hopper(Nilaparvata lugens) Cpd T1.067, Table 1 of ratio Cpd. Cpd.WO2009/049851, Al:PGR P1.2, P1.29, wherein G is (Moddus) ppm Al Table P1Table P1 COOCH₂CH₃ 200 90 100 100 100 80 100 98 50 62 100 100 25 37 9897 12.5 65 98 98  15:1 200 87 100 100 7.5:1 100 77 100 100 1.25:1  50 3398 100 1.9:1 25 10 97 100 0.9:1 12.5 5 80 98

Tank mixing of the PGR Moddus with these insecticides does not adverselyaffect the brown plant hopper control of test compounds.

TABLE B2-2 phytotoxicity on rice no. of leaves with chlorosis (mean of 4reps) Cpd. T1.067, Table 1 of Cpd. Cpd. WO2009/049851, ratio P1.2,P1.29, wherein G is Al:PGR ppm Al Table P1 Table P1 COOCH₂CH₃ 200 0 7 2100 7 15 4 50 14 15 11 25 12 2 15 12.5 0 0 12  15:1 200 0 1 0 7.5:1 1000 5 0 1.25:1  50 2 3 2 1.9:1 25 4 0 2 0.9:1 12.5 0 0 5

Data demonstrate that the combination with Moddus reduces or evenabolishes the phyototoxicity on rice.

1. A pesticidal composition comprising (a) a pesticidal effective amountof at least one compound of formula I

in which Q is i or ii or iii

X, Y and Z independently of each other are C₁₋₄alkyl, C₃₋₆cycloalkyl,C₁₋₄haloalkyl, C₁₋₄ alkoxy, halogen, phenyl or phenyl substituted byC₁₋₄alkyl, C₁₋₄haloalkyl, halogen or cyano; m and n, independently ofeach other, are 0, 1, 2 or 3 and m+n is 0, 1, 2 or 3; G is hydrogen, ametal, an ammonium, a sulfonium or a latentiating group; R is hydrogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆cyanoalkyl, benzyl, C₁₋₄alkoxy(C₁₋₄)alkyl,C₁₋₄alkoxy(C₁₋₄)alkoxy(C₁₋₄)alkyl or a group selected from G; A isC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄alkyl, orC₃₋₆cycloalkyl-(C₁₋₄)alkyl where in the cycloalkyl moiety a methylenegroup is replaced by O, S or NR₀, where R₀ is C₁₋₆alkyl or C₁₋₆alkoxy,or A is C₂₋₆alkenyl, C₂₋₆haloalkenyl, C₃₋₆alkynyl, C₁₋₆cyanoalkyl,benzyl, C₁₋₄alkoxy(C₁₋₄)alkyl, C₁₋₄alkoxy(C₁₋₄)alkoxy(C₁₋₄)alkyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₃₋₆cycloalkylcarbonyl, N-di(C₁₋₆alkyl)carbamoyl,benzoyl, C₁₋₆alkylsulfonyl, phenylsulfonyl, C₁₋₄alkylthio(C₁₋₄alkyl,C₁₋₄alkylsulfinyl(C₁₋₄)alkyl or C₁₋₄alkylsulfonyl(C₁₋₄)alkyl; and when Qis ii A may also be hydrogen, furanyl-(C₁₋₄alkyl,tetrahydro-thiofuranyl, tetrahydro-thiopyranyl or1-(C₁₋₄)alkoxy-piperidin-4-yl; and R₁, R₂, R₃ and R₄, independently ofeach other, are hydrogen or methyl; or an agrochemically acceptable saltor an N-oxide thereof, and (b) a plant growth regulator, where the ratioof compound of formula I to plant growth regulator is from 20:1 to 1:25.2. A composition according to claim 1, wherein the plant growthregulator is selected from antiauxins, auxins, cytokinins, defoliants,ethylene inhibitors, growth inhibitors, growth retardants, growthstimulators, unclassified plant regulators, plant activators,salicylates, jasmonates, cis-jasmonates, plant peptide hormones,polyamines; strigolactones and nitric oxide donors.
 3. A compositionaccording to claim 1, wherein the plant growth regulator is selectedfrom trinexapac ethyl, 1-methylcyclopropene, ethephon, chlormequat andacibenzolar-5-methyl.
 4. A composition according to claim 3, wherein theplant growth regulator is selected from trinexapac ethyl,1-methylcyclopropene, chlormequat and acibenzolar-5-methyl.
 5. Acomposition according to claim 1, wherein the ratio compound of formulaI to plant growth regulator is from 1:1 to 1:20.
 6. A method ofcombating and controlling pests which comprises treating the pests orthe locus of the pests or the plant susceptible to attack by a pest withan insecticidally, nematicidally or mollusicidally effective amount of acomposition according to claim 1.